Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms

*Vera Nevzorova, Tatiana Brodskaya and Eugeny Gilifanov*

## **Abstract**

This chapter describes endothelium-related and neuro-mediated mechanisms of emphysema development in chronic obstructive pulmonary disease (COPD) and smoking on the basis of previously completed studies, literature data, and own researches. As components of neurogenic inflammation in the processes of tissue remodeling in emphysema, we describe the distribution and activity of the substance P, neurokinin-1 and its receptor, tissue metalloproteinases and their tissue inhibitors in the lungs during the entire experimental period, the modeling of COPD in rats with a smoking model. We also analyzed the content of neurokinin system markers, the localization, and markers of tissue metalloproteinases in human lung tissue structures. We have confidence that there is a special morphofunctional continuum of development of lower respiratory tract remodeling in response to chronic exposure to tobacco smoke and the development of inflammation in COPD. New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. Research in this direction should be continued to allow approaches to the development of preventive and therapeutic strategies for emphysema.

**Keywords:** COPD, smoking, emphysema, remodeling, neuro-mediated, endothelium, neurokinins, metalloproteinases

## **1. Introduction**

Emphysema, or destruction of the gas-exchanging surfaces of the alveoli, is one of the typical manifestations of chronic obstructive pulmonary disease (COPD). Emphysema is a pathological term that is often used clinicaly, has great medical significance and describes only one of several structural abnormalities present in patients [1]. Many previous definitions of COPD have emphasized the terms "emphysema" and "chronic bronchitis," which are not included in the definition used in the last GOLD report. In GOLD 2018, COPD was defined as a common, preventable, and treatable disease that is characterized by persistent respiratory

symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases [1]. It was mentioned that chronic respiratory symptoms also exist in individuals with normal spirometry and a significant number of smokers without airflow limitation have structural evidence of lung disease manifested by the varying presence of emphysema, airway wall thickening, and gas trapping [2–4]. Really, smoking is a major risk factor for COPD, and it plays an important role in lung tissue destruction development. Some experiments prove that aggressive pollutants of tobacco smoke (benzopyrene, peroxynitrite, acrolein, cyanides, peroxides, etc.) can cause direct damage to endothelial cells due to expression of adhesion molecules on their surface and intensification of lipid peroxidation [2, 5–7]. But the main underlying cause of structural changes is chronic inflammation, which is confirmed by numerous studies [1, 4–6]. Even in mild COPD, or in smokers susceptible to emphysema [7, 8], there are significant abnormalities in pulmonary microvascular blood flow that worsen with disease progression [9].

It was proven that vascular endothelium actively participates in inflammatory reactions in COPD [10–13]. It was a systemized data about cigarette smoke as an endothelial toxin and activator [14]. Endothelium is one of the direct participants of development and maintenance of chronic inflammation. Oxidized lipoproteins in the tunica intima of the vessel work as attractants for chemotaxis of leukocytes and monocytes that start to produce pro-inflammatory cytokines in big amounts. These processes trigger systemic inflammatory response that leads to irreversible thickening of the vessel walls and deterioration of their mechanical properties. Chronic exposure to tobacco smoke and the products of combustion of tobacco lead to chronic system inflammatory reaction, oxidative stress, endothelial dysfunction, and morphofunctional damage of target organs. Nowadays the connection between endothelium-related mechanisms and emphysema forming, and progression in COPD is well known. Recent studies are approaching the description of the neuromediated mechanisms of emphysema development in COPD.

In this chapter we have analyzed data from researchers and shared our own research on the study of endothelium and the neuro-mediated mechanisms of emphysema development in COPD and smoking.

## **2. Endothelium-related and neuro-mediated mechanisms of emphysema development in COPD and smoking: research data**

The participation of endothelial dysfunction and injury in emphysema development in COPD has been described since 2000 and early [15, 16]. And the interest of researchers to the problem of the involvement of the endothelium in the pathogenesis of COPD has not decreased over the past decades. So, for the request "endothelium + emphysema" (in the title and/or abstract), the well-known online resource of the library PubMed offers 117 publications, of which 23 after 2015. For the request "endothelium + COPD," it offers 335 publications, of which 72 after 2015, and for the request "endothelium + smoking," it offers 1859 publications, of which 188 after 2015. This indicates the relevance of this area of research and demonstrates the hopes of researchers finding new opportunities for therapeutic and prophylactic effects on this relationship in the pathogenesis of tobacco-related lesions, COPD, and emphysema [17–23].

All disorders begin with local and systemic inflammation, hypoxia and oxidative stress, and lead to an imbalance of proteases-antiproteases, loss of recovery and destruction of lung tissue. Activation and dysfunction of the endothelium involves, first of all, imbalance of the endothelium and its associated mechanisms, which

**17**

recognized.

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

would like to pay attention on some endothelium-dependent factors.

content of сirculated endothelial cells, an endothelial repair factor [11, 30].

processes in the pathogenesis of emphysema.

described previously [4, 10–13, 18–20, 22, 23, 26, 27].

Endothelial dysfunction and damage are also caused by the acute effects of cigarette smoke long before the development of emphysema in animal models. Brief exposure of mice to cigarette smoke exacerbates lipopolysaccharide- and *Pseudomonas aeruginosa*-induced acute lung injury in vivo, and cigarette smoke extract increases the permeability of endothelial monolayers in vitro [14, 27]. Moreover, a recent study identified cigarette smoke-induced apoptosis of endothelial cells in the lungs of mice exposed chronically to cigarette smoke and COPD patients [11]. Thus, data from both animal models of COPD and COPD patients and controls support the hypothesis that endothelial dysfunction and injury are key

In **Table 1** we composed information on key endothelium-related agents that take into account the mechanisms of emphysema development in COPD, well

The mechanisms of the inclusion of neurokinins and related substances in neurogenic inflammation and destruction at different stages of COPD are much less known. Moreover, in recent studies, descriptions of the neuro-mediated mechanisms for the development of emphysema in COPD and smoking have become

It is known that tobacco smoke is a powerful inducer of the destruction of the respiratory epithelium throughout, followed by its morphofunctional remodeling [4, 31, 32]. Initiation of cell and tissue injury processes in prolonged exposure to smoking can take place due to excess release of neurotransmitters from sensitive afferent nerve fibers of the nervous vagus system. A large proportion (75%) of such fibers belong to the type of nonmyelinated or C-fibers, the sources of which are small neurons of the knotted and jugular ganglia, which synthesize neuropeptide transmitters or neurokinins (such as substance P (SP), a peptide genetically related to calcitonin (CGRP) and neurokinin (A)) [33, 34]. Afferent influences are primarily aimed at maintaining the structural and functional homeostasis of the respiratory system by stimulating the secretion of mucus from the submucous

are due to the following disorders in the pathogenesis of COPD [4]. Separately, we

Prolonged damage to endotheliocytes by aggression factors (persistent inflammation, hypoxia, oxidative stress, an imbalance in the protease-antiprotease system, etc.) leads to their death and anatomical reduction of the capillary bed, which is a component of emphysematous lung changes. Pathobiology of small vessels in COPD, in addition to inflammatory and hypercoagulative changes, is characterized by intimal thickening, arteriole muscularization, a decrease in the number of capillaries, and a decrease in blood vessels [13, 15]. Delivering a VEGF receptor (VEGFR) antagonist to rats led rapidly to air space enlargement and pruning of the pulmonary arterial tree [23, 24]. VEGF is a trophic factor that is crucial for the survival of endothelial cells. The experiment demonstrated that prolonged blockade of VEGF receptors leads to apoptosis of septal endothelial cells and emphysema [16, 25]. Subsequent studies of emphysematous lungs confirmed that COPD patients have decreased lung levels of VEGF, reduced expression of VEGFR in pulmonary endothelial cells and apoptotic alveolar septal cells, and reduced expression of hypoxiainducible factor-1α (HIF-1α), a transcription factor that drives the expression of genes involved in endothelial function including VEGFRs [26, 27]. It has been shown that along with the progression of emphysema, degenerative changes in the walls of the aorta develop, including its dilatation and aneurysmatization [28, 29]. These facts indicate that among other circumstances, an important role in the pathogenesis of emphysema belongs to endotheliocytes and VEGF. Moreover, it has been described that the presence of emphysema in patients with COPD is associated with a reduced

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

#### *Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

are due to the following disorders in the pathogenesis of COPD [4]. Separately, we would like to pay attention on some endothelium-dependent factors.

Prolonged damage to endotheliocytes by aggression factors (persistent inflammation, hypoxia, oxidative stress, an imbalance in the protease-antiprotease system, etc.) leads to their death and anatomical reduction of the capillary bed, which is a component of emphysematous lung changes. Pathobiology of small vessels in COPD, in addition to inflammatory and hypercoagulative changes, is characterized by intimal thickening, arteriole muscularization, a decrease in the number of capillaries, and a decrease in blood vessels [13, 15]. Delivering a VEGF receptor (VEGFR) antagonist to rats led rapidly to air space enlargement and pruning of the pulmonary arterial tree [23, 24]. VEGF is a trophic factor that is crucial for the survival of endothelial cells. The experiment demonstrated that prolonged blockade of VEGF receptors leads to apoptosis of septal endothelial cells and emphysema [16, 25]. Subsequent studies of emphysematous lungs confirmed that COPD patients have decreased lung levels of VEGF, reduced expression of VEGFR in pulmonary endothelial cells and apoptotic alveolar septal cells, and reduced expression of hypoxiainducible factor-1α (HIF-1α), a transcription factor that drives the expression of genes involved in endothelial function including VEGFRs [26, 27]. It has been shown that along with the progression of emphysema, degenerative changes in the walls of the aorta develop, including its dilatation and aneurysmatization [28, 29]. These facts indicate that among other circumstances, an important role in the pathogenesis of emphysema belongs to endotheliocytes and VEGF. Moreover, it has been described that the presence of emphysema in patients with COPD is associated with a reduced content of сirculated endothelial cells, an endothelial repair factor [11, 30].

Endothelial dysfunction and damage are also caused by the acute effects of cigarette smoke long before the development of emphysema in animal models. Brief exposure of mice to cigarette smoke exacerbates lipopolysaccharide- and *Pseudomonas aeruginosa*-induced acute lung injury in vivo, and cigarette smoke extract increases the permeability of endothelial monolayers in vitro [14, 27]. Moreover, a recent study identified cigarette smoke-induced apoptosis of endothelial cells in the lungs of mice exposed chronically to cigarette smoke and COPD patients [11]. Thus, data from both animal models of COPD and COPD patients and controls support the hypothesis that endothelial dysfunction and injury are key processes in the pathogenesis of emphysema.

In **Table 1** we composed information on key endothelium-related agents that take into account the mechanisms of emphysema development in COPD, well described previously [4, 10–13, 18–20, 22, 23, 26, 27].

The mechanisms of the inclusion of neurokinins and related substances in neurogenic inflammation and destruction at different stages of COPD are much less known. Moreover, in recent studies, descriptions of the neuro-mediated mechanisms for the development of emphysema in COPD and smoking have become recognized.

It is known that tobacco smoke is a powerful inducer of the destruction of the respiratory epithelium throughout, followed by its morphofunctional remodeling [4, 31, 32]. Initiation of cell and tissue injury processes in prolonged exposure to smoking can take place due to excess release of neurotransmitters from sensitive afferent nerve fibers of the nervous vagus system. A large proportion (75%) of such fibers belong to the type of nonmyelinated or C-fibers, the sources of which are small neurons of the knotted and jugular ganglia, which synthesize neuropeptide transmitters or neurokinins (such as substance P (SP), a peptide genetically related to calcitonin (CGRP) and neurokinin (A)) [33, 34]. Afferent influences are primarily aimed at maintaining the structural and functional homeostasis of the respiratory system by stimulating the secretion of mucus from the submucous

*Update in Respiratory Diseases*

symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases [1]. It was mentioned that chronic respiratory symptoms also exist in individuals with normal spirometry and a significant number of smokers without airflow limitation have structural evidence of lung disease manifested by the varying presence of emphysema, airway wall thickening, and gas trapping [2–4]. Really, smoking is a major risk factor for COPD, and it plays an important role in lung tissue destruction development. Some experiments prove that aggressive pollutants of tobacco smoke (benzopyrene, peroxynitrite, acrolein, cyanides, peroxides, etc.) can cause direct damage to endothelial cells due to expression of adhesion molecules on their surface and intensification of lipid peroxidation [2, 5–7]. But the main underlying cause of structural changes is chronic inflammation, which is confirmed by numerous studies [1, 4–6]. Even in mild COPD, or in smokers susceptible to emphysema [7, 8], there are significant abnormalities in pulmonary microvascular

It was proven that vascular endothelium actively participates in inflammatory reactions in COPD [10–13]. It was a systemized data about cigarette smoke as an endothelial toxin and activator [14]. Endothelium is one of the direct participants of development and maintenance of chronic inflammation. Oxidized lipoproteins in the tunica intima of the vessel work as attractants for chemotaxis of leukocytes and monocytes that start to produce pro-inflammatory cytokines in big amounts. These processes trigger systemic inflammatory response that leads to irreversible thickening of the vessel walls and deterioration of their mechanical properties. Chronic exposure to tobacco smoke and the products of combustion of tobacco lead to chronic system inflammatory reaction, oxidative stress, endothelial dysfunction, and morphofunctional damage of target organs. Nowadays the connection between endothelium-related mechanisms and emphysema forming, and progression in COPD is well known. Recent studies are approaching the description of the neuro-

In this chapter we have analyzed data from researchers and shared our own research on the study of endothelium and the neuro-mediated mechanisms of

**2. Endothelium-related and neuro-mediated mechanisms of emphysema** 

The participation of endothelial dysfunction and injury in emphysema develop-

All disorders begin with local and systemic inflammation, hypoxia and oxidative

stress, and lead to an imbalance of proteases-antiproteases, loss of recovery and destruction of lung tissue. Activation and dysfunction of the endothelium involves, first of all, imbalance of the endothelium and its associated mechanisms, which

ment in COPD has been described since 2000 and early [15, 16]. And the interest of researchers to the problem of the involvement of the endothelium in the pathogenesis of COPD has not decreased over the past decades. So, for the request "endothelium + emphysema" (in the title and/or abstract), the well-known online resource of the library PubMed offers 117 publications, of which 23 after 2015. For the request "endothelium + COPD," it offers 335 publications, of which 72 after 2015, and for the request "endothelium + smoking," it offers 1859 publications, of which 188 after 2015. This indicates the relevance of this area of research and demonstrates the hopes of researchers finding new opportunities for therapeutic and prophylactic effects on this relationship in the pathogenesis of tobacco-related

blood flow that worsen with disease progression [9].

mediated mechanisms of emphysema development in COPD.

**development in COPD and smoking: research data**

emphysema development in COPD and smoking.

lesions, COPD, and emphysema [17–23].

**16**


#### **Table 1.**

*Endothelium-related Components of emphysema development in COPD and smoking [4, 10–13, 18–20, 22, 23, 26, 27].*

glands and goblet cells, contractility of smooth muscles, vascular permeability, modulation of immune cascades, etc. [34–36]. It is known that afferent fibers (C-fibers) are extremely sensitive to the effects of irritants that make up tobacco smoke [37]. In a situation of prolonged and/or intense stimulation of sensory

**19**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

**Agents Origin, localization Physiological effects and potential role** 

**in emphysema pathogenesis in COPD**

Belongs to the family of tachykinins, sensory peptides. Induces vasodilation and transudation of blood plasma in the

Induces chemotaxis of monocytes, neutrophils, and eosinophils and stimulates macrophages to produce mediators of inflammation and

Powerful mast cell stimulator, causing their degranulation. Sources and release of histamine and cytokine synthesis (IL-6). Takes part in neurogenic inflammation when stimulating the production of IgA from B lymphocytes and cytokines from T-helper cells. Enhances the release of acetylcholine from the postganglionic cholinergic nerves of the respiratory tract It causes smooth muscle contraction, secretion of submucous glands, vasodilation, and increased vascular

Tobacco smoking inhibits the activity of the enzyme endopeptidase, which enhances the activity of SP

Belongs to the family of tachykinins, sensory peptides. Contraction of smooth muscles; secretion of submucous glands; vasodilation; increased vascular permeability; stimulation of cholinergic nerves, mast cells, B and T lymphocytes, and macrophages; eosinophil chemoattraction; and adhesion of neutrophils in the vessels of the respiratory tract with activation following

Reduces the frequency of vibrations of ciliary cells induced by cholinergic nerves, providing an inhibitory effect on

vasoconstriction and can also stimulate the secretion of certain glands in the

The tachykinin receptor NK1, with the highest affinity for SP. SP, in turn, is a powerful mast cell stimulator, causing their degranulation, and induces the chemotaxis of monocytes, neutrophils, eosinophils, and stimulates macrophages to produce inflammatory mediators and

Sympathetic reflexes cause

trachea and bronchi

neutrophilic elastase

respiratory tract.

neutrophil elastase.

permeability.

these nerves

**References**

[40, 45, 48, 49]

[44, 50, 51]

[38, 39, 48]

[40, 42, 45]

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

cells.

Sensitive nerve endings. SP receptors on respiratory and glandular epithelial cells and endothelial

Neurokinin receptor-1 affixed to SP is found in submucous glands, and SP release from nociceptive nerves is responsible for secretion of glands

The highest density in the nerve fibers around the arteries. Tachykinin receptor subtypes NK1, NK2,

It is produced in some of the upper cervical ganglia and the bodies of the main palatine

Sympathetic nerves contain either norepinephrine or norepinephrine and neuropeptide Y

receptor mRNA is found in the pulmonary arteries, veins, and human bronchi, in the endothelium of the veins and arteries, and in the smooth muscles of the bronchi, as well as in lymphocytes, macrophages, and mastocytes

and NK3

cells

Receptor NK1 NK1 tachykinin

Neurokinins Substance P (SP)

Neurokinins Neurokinin А

Neuropeptide



*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

*Update in Respiratory Diseases*

Selectins: E-selectin (CD62Е), Р-selectin (CD62Р), L-selectin

Thrombomodulin (CD141)

Circulated endothelial

Vascular endothelial growth factor (VEGF)

Neutrophil elastase (catepsin G, proteinase 3)

Matrix

metalloproteinases (ММP-1, ММP-2, ММP-9)

(CD62L)

cells

Nitric oxide (NO) In main, endothelial cells and other cells

Endothelinum-1 (ET-1) Endothelial cells, bronchial

sPECAM-1 Endothelial cells,

epithelium, alveolar macrophages

lymphocytes, platelets, macrophages, granulocytes, T/NK-cell megakaryocytes, fibroblasts, osteoclasts

Endothelial cells from vascular wall, activated bone

Neutrophils, monocytes, Т lymphocytes, endothelial cells, vascular smooth muscles cells

Endothelial cells, macrophages, neutrophils, monocytes, fibroblasts, keratinocytes, osteoblasts

marrow

**18**

**Table 1.**

glands and goblet cells, contractility of smooth muscles, vascular permeability, modulation of immune cascades, etc. [34–36]. It is known that afferent fibers (C-fibers) are extremely sensitive to the effects of irritants that make up tobacco smoke [37]. In a situation of prolonged and/or intense stimulation of sensory

*Endothelium-related Components of emphysema development in COPD and smoking [4, 10–13, 18–20, 22, 23, 26, 27].*

**Components Origin, localization Physiological effects and potential role at** 

**pathogenesis emphysema in COPD**

Vasorelaxation, vasoprotection, antiinflammatory, anti-adhesion, reparation.

Activates receptors on smooth cells, encouraging stable vasoconstriction and increase of endothelium adhesively

Plays a basic role in lymphocyte adhesion to vascular wall with followed effects

(strengthens the capacity to migration, leukocyte adhesion to activated endothelium in inflammation)

C, acts as anticoagulant across activation factors fVa, fVIIIа, fXa, and fXIIIa

Can be as the factor of reparation according to inflammatory processes and as the factor of injury to the endothelium and other tissues due to activated phenotype

provides their effects across receptors' endothelial cell and expression of VEGF regulated by hypoxia, chronic inflammation, hypercoagulation, etc. In chronic processes, function can be an

Stimulates apoptosis and phagocytosis and promotes development of emphysema

Decreases migration of T lymphocytes and neutrophil to inflammation area, factor of decelerating of phagocytosis. Function from protection to damaging. Can cause damage to tissues, development of emphysema, and

Involved in normal degradation of matrix proteins elastin, collagen, fibronectin,

Endothelin antagonist

Activated endothelial cells Regulation of leukocyte adhesion

Endothelial cells Interacts with thrombin, activates protein

Endothelial cells Main inductor of angiogenesis, VEGF,

imperfect character

mucus hypersecretion

laminin, and proteoglycans

fibronectin, and elastin

Contributes to release TNF-α from macrophages, that results to neutrophils recruiting and production neutrophil elastase, that leads to damage tissues, development emphysema. Involved in degradation of type IV collagen,


#### **Table 2.**

*Potential neuro-mediated mechanisms of emphysema development in COPD and tobacco smoking.*

fibers, excessive release of neuropeptide mediator is accompanied by a number of plastic and destructive processes due to a cascade of pathological reactions of neurogenic inflammation [38, 39]. In addition to substance P of neuronal origin, neuropeptides from cells of the immune system—eosinophils, basophils, monocytes, macrophages and lymphocytes—join the realization of neurogenic inflammation [38, 40, 41]. The obtained data indicate the role of the disturbance of the activity of the neurokinin system in the development and maintenance of morphofunctional changes in the pathology of the respiratory tract associated with smoking [42–46]. Chronic exposure to cigarette smoke has been shown to increase SP expression in neurons of the central nervous system [35–37] and simultaneously inhibits the activity of enzymes that metabolize neurokinins [39, 40, 43]. According to experimental study, even low concentrations of cigarette smoke significantly reduce the topical activity of neuronal endopeptidase and increase the concentration of CP in the respiratory tract [35]. The contribution of excessive sensitivity of NK1 receptors in the airways to the development of bronchoconstriction under the influence of tobacco smoke irritants and/or during bronchial asthma has been proven [42, 43, 47]. At the same time, the components and mechanisms of neurogenic inflammation in the development of emphysema associated with prolonged exposure to tobacco smoke are poor and fragmentary in the literature.

In **Table 2** we have tried to compose information about potential neuro-mediated mechanisms of emphysema development in COPD and tobacco smoking.

### **3. Mechanisms of neurogenic inflammation in the tissue remodeling processes in emphysema: own researches**

#### **3.1 Study of the neurogenic inflammation mechanisms in the emphysema formation in the experiment**

To study the contribution of the components of neurogenic inflammation to the processes of tissue remodeling in pulmonary emphysema associated with smoking, an experimental model of long-term tobacco smoking in vivo in rats was reproduced. The experiment was performed in appliance with the model D. According to Zheng [53] in our own modification [54], the duration of exposure to tobacco smoke in terms of human life is 12 years. The features of the

**21**

State Medical University.

cells, lymphocytes, and macrophages.

smoking and control animals (**Table 3**).

and adventitia of pulmonary vessels (**Figure 2E**).

in **Figure 1**.

**Figure 1.**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

distribution and activity of SP, NK1, MMP-2, MMP-9, and TIMP-2 in the tissues of the mucous membrane of the lungs were performed using the immunoperoxidase method on cryostat sections of 15 μm in thickness according to standard methods. The following primary antibodies were used: anti-SP (Abcam, ab 14184, 1:200, США), anti-NK1 (Chemicon AB 5060, 1:500, USA), anti-MMP2 (rabbit polyclonal, ThermoScientific), anti-MMP9 (rabbit polyclonal, ThermoScientific, rb-9234-p, 1:200), anti-TIMP2 (rabbit polyclonal, Abcam, ab61224, 1:100), secondary biotinylated antibodies (ThermoScientific, 1:200), streptavidin peroxidase (ThermoScientific), and chromogen (Peroxidase Substrate Kit, VectorNovaRED, SK-4800). Morphological studies were performed in the laboratory of the Pacific

*The lung (A, B) and bronchi (C, D) of animals in the control group (A, C) and rats with the DTC model* 

*(B, D). Coloring: hematoxylin-eosin. Scale: A, B (500 microns); C, D (100 microns).*

The results of morphological studies of the bronchopulmonary system of rats in the control group and with the model of long-term tobacco smoking are presented

Morphological changes in the lungs of rats with a long-term tobacco smoking model are focal. Over the entire area of the slice of the lungs, there are fields with pronounced emphysematous changes, accompanied by loss of the integrity of the alveoli and the formation of large emphysematous expansions, an increase in the thickness of the interalveolar septa (**Figure 1B, D**). In other parts of the lung parenchyma, there are signs of swelling and/or hemorrhagic impregnation in peribronchial spaces. Cellular composition contains cells of immune inflammation—plasma

The distribution of the components of the neurokinin system of rats obtained by morphological examination of the bronchi and lungs coincides with the previously described data [55] and is shown in **Figure 2**. Nerve fibers secreting SP are presented in the subepithelial zones of the bronchi (**Figure 2A**); their penetration is recorded in the epithelial layer (**Figure 2B**), pulmonary parenchyma (**Figure 2D**),

The morphometry of the components of the neurokinin system in the bronchopulmonary system of rats was compared with the model of long-term tobacco

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

#### **Figure 1.**

*Update in Respiratory Diseases*

Receptor NK2 Receptor NK3

**Table 2.**

fibers, excessive release of neuropeptide mediator is accompanied by a number of plastic and destructive processes due to a cascade of pathological reactions of neurogenic inflammation [38, 39]. In addition to substance P of neuronal origin, neuropeptides from cells of the immune system—eosinophils, basophils, monocytes, macrophages and lymphocytes—join the realization of neurogenic inflammation [38, 40, 41]. The obtained data indicate the role of the disturbance of the activity of the neurokinin system in the development and maintenance of morphofunctional changes in the pathology of the respiratory tract associated with smoking [42–46]. Chronic exposure to cigarette smoke has been shown to increase SP expression in neurons of the central nervous system [35–37] and simultaneously inhibits the activity of enzymes that metabolize neurokinins [39, 40, 43]. According to experimental study, even low concentrations of cigarette smoke significantly reduce the topical activity of neuronal endopeptidase and increase the concentration of CP in the respiratory tract [35]. The contribution of excessive sensitivity of NK1 receptors in the airways to the development of bronchoconstriction under the influence of tobacco smoke irritants and/or during bronchial asthma has been proven [42, 43, 47]. At the same time, the components and mechanisms of neurogenic inflammation in the development of emphysema associated with prolonged exposure to tobacco smoke are poor and fragmentary in

*Potential neuro-mediated mechanisms of emphysema development in COPD and tobacco smoking.*

NK2 receptors

**Agents Origin, localization Physiological effects and potential role** 

NK2 receptor mRNA is abundantly expressed in the human bronchi and weakly in the pulmonary veins and

arteries NK3 tachykinin receptor mRNA is found in the pulmonary arteries, veins, and human bronchi

**in emphysema pathogenesis in COPD**

The tachykinin receptor NK2, with the highest affinity for neurokinin A. Tachykinin receptor NK3, with the highest affinity for neurokinin B The release of histamine from mouse mast cells is mediated through tachykinin **References**

[40, 42, 45, 52]

In **Table 2** we have tried to compose information about potential neuro-mediated mechanisms of emphysema development in COPD and tobacco smoking.

**3. Mechanisms of neurogenic inflammation in the tissue remodeling** 

**3.1 Study of the neurogenic inflammation mechanisms in the emphysema** 

To study the contribution of the components of neurogenic inflammation to the processes of tissue remodeling in pulmonary emphysema associated with smoking, an experimental model of long-term tobacco smoking in vivo in rats was reproduced. The experiment was performed in appliance with the model D. According to Zheng [53] in our own modification [54], the duration of exposure to tobacco smoke in terms of human life is 12 years. The features of the

**processes in emphysema: own researches**

**formation in the experiment**

**20**

the literature.

*The lung (A, B) and bronchi (C, D) of animals in the control group (A, C) and rats with the DTC model (B, D). Coloring: hematoxylin-eosin. Scale: A, B (500 microns); C, D (100 microns).*

distribution and activity of SP, NK1, MMP-2, MMP-9, and TIMP-2 in the tissues of the mucous membrane of the lungs were performed using the immunoperoxidase method on cryostat sections of 15 μm in thickness according to standard methods. The following primary antibodies were used: anti-SP (Abcam, ab 14184, 1:200, США), anti-NK1 (Chemicon AB 5060, 1:500, USA), anti-MMP2 (rabbit polyclonal, ThermoScientific), anti-MMP9 (rabbit polyclonal, ThermoScientific, rb-9234-p, 1:200), anti-TIMP2 (rabbit polyclonal, Abcam, ab61224, 1:100), secondary biotinylated antibodies (ThermoScientific, 1:200), streptavidin peroxidase (ThermoScientific), and chromogen (Peroxidase Substrate Kit, VectorNovaRED, SK-4800). Morphological studies were performed in the laboratory of the Pacific State Medical University.

The results of morphological studies of the bronchopulmonary system of rats in the control group and with the model of long-term tobacco smoking are presented in **Figure 1**.

Morphological changes in the lungs of rats with a long-term tobacco smoking model are focal. Over the entire area of the slice of the lungs, there are fields with pronounced emphysematous changes, accompanied by loss of the integrity of the alveoli and the formation of large emphysematous expansions, an increase in the thickness of the interalveolar septa (**Figure 1B, D**). In other parts of the lung parenchyma, there are signs of swelling and/or hemorrhagic impregnation in peribronchial spaces. Cellular composition contains cells of immune inflammation—plasma cells, lymphocytes, and macrophages.

The distribution of the components of the neurokinin system of rats obtained by morphological examination of the bronchi and lungs coincides with the previously described data [55] and is shown in **Figure 2**. Nerve fibers secreting SP are presented in the subepithelial zones of the bronchi (**Figure 2A**); their penetration is recorded in the epithelial layer (**Figure 2B**), pulmonary parenchyma (**Figure 2D**), and adventitia of pulmonary vessels (**Figure 2E**).

The morphometry of the components of the neurokinin system in the bronchopulmonary system of rats was compared with the model of long-term tobacco smoking and control animals (**Table 3**).

#### **Figure 2.**

*Distribution of SP- and NK1-reactive structures in the bronchopulmonary system of rats. Coloring: immunoperoxidase reaction on SP; repainting, hematoxylin-eosin. Scale: A, 100 microns; B–E, 50 microns.*

The content of SP-containing fibers and NK1-positive structures in the control group and in the model of long-term tobacco smoking shows an ambiguous pattern. An increase in the distribution area of SP-immunopositive nerve fibers in the lungs and bronchi of experimental animals was found to be 10.7 and 9.4%, respectively, compared with the control group. The most significant increase in fiber density was observed in the adventitia of pulmonary parenchyma vessels compared with other structures. Being a vasodilator, substance P increases vascular permeability and promotes adhesion and penetration of leukocytes into the surrounding tissues for the realization of local immune reactions involved in the development of destructive processes in the pulmonary parenchyma. Regarding NK1-positive elements, it should be noted that there is no change in their content in the lung tissue and a moderate increase in the density in the bronchial wall against the background of a decrease in the total number and NK1-immunoreactive tissue basophils. Obviously, substance P plays a key role in the implementation of neurogenic inflammation processes in chronic exposure to tobacco smoke. The established pattern of changes in NK1-positive structures can be explained by the ability of SP to cause mast cell degranulation and NK1 receptordependent release of histamine and serotonin involved in local inflammatory answer.

**23**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

**Indicator Bronchi Lungs**

0.36

0.03

**Control Experiment** 

**(long-term smoking model)**

5.59 ± 0.14\* 4.60 ±

0.31 ± 0.03\* 0.16 ±

0.29

0.016

92.68 ± 19.26

129.53 ± 19.64

**Control Experiment (long-**

**term smoking model)**

5.10 ± 0.34\*

0.16 ± 0.02

76.39 ± 15.74\*

106.93 ± 7.64\*

One of the leading stimulators of the synthesis of substance P in the model of long-term tobacco smoking is hypoxia which changes the humoral regulation of blood flow [55]. SP can adjust the change in vessel diameter at the unchanged vascular wall using an axon reflex for adequate blood flow at a given point in time. However, when the architectonics of the vascular wall changes, the SP loses its function as a regulator and can participate in both excessive vasodilation and paradoxi-

*Morphometric characteristics of SP- and NK1-immunoreactive structures in the bronchopulmonary system of rats.*

In the development of the structural remodeling of the respiratory system, there are several morphological phenomena that accompany this process and are the basis for the development of reversible and irreversible morphofunctional changes. These include thinning of the epithelial layer, development of subepithelial fibrosis, an increase in smooth muscle thickness, an increase in the number and/or size of the submucosal glands, and the activation of angiogenesis processes [56]. In the pathogenesis of the changes taking place, great importance is attached to the activity of the enzymes of the extracellular matrix, which ensure the degradation of its interstitial proteins. Modern advances in proteomics have shown that for normal development, physiological renewal, restoration of healthy tissues, and the formation of pathological changes in tissue morphology, two groups of proteins are leading—MMPs and their tissue inhibitors [57, 58]. MMPs are a family of 20 zinc and calcium-dependent endopeptidases capable of cleaving almost all components of the extracellular matrix of connective tissues [59]. The level of synthesis and secretion of MMP into the extracellular space is regulated by transcription factors, and their proteolytic activity depends on the chemical transformations of the enzyme molecule in the interstitial space. As a result, either activation of the proenzymes or inhibition of their active forms can be observed. Depending on the type of protein metabolized, MMP can be divided into collagenases (MMP-1, MMP-8, and MMP-13), gelatinase (MMP-2 and MMP-9), stromalins (MMP-3 and MMP-10), etc. [60, 61]. In mammals there are four known TIMPs that inhibit all MMPs in a 1:1 ratio by strong covalent bonding [62]. It is believed that the balance of proteolytic and antiproteolytic mechanisms maintained in different tissues and organs is carried out by a specific set of intercellular matrix enzymes and their inhibitors [59, 63]. On the other hand, each process has a specific set of depressed matrix proteolytic enzymes. In this regard, great prospects in creating targeted therapy for many pathological processes are associated with the determination of the tissue specificity of the enzymes of the extracellular matrix and the identification of patterns

of changes in their activity during the development of pathology.

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

SP distribution area (%) 5.11 ±

NK1 distribution area (%) 0.27 ±

of the

*The differences are significant with р < 0.05.*

NK1-positive mast cells (in

of the tissue)

General population of tissue basophils (in 1 mm3

1 mm3

tissue)

*\**

**Table 3.**

cal vasoconstriction.

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*


#### **Table 3.**

*Update in Respiratory Diseases*

**22**

**Figure 2.**

The content of SP-containing fibers and NK1-positive structures in the control group and in the model of long-term tobacco smoking shows an ambiguous pattern. An increase in the distribution area of SP-immunopositive nerve fibers in the lungs and bronchi of experimental animals was found to be 10.7 and 9.4%, respectively, compared with the control group. The most significant increase in fiber density was observed in the adventitia of pulmonary parenchyma vessels compared with other structures. Being a vasodilator, substance P increases vascular permeability and promotes adhesion and penetration of leukocytes into the surrounding tissues for the realization of local immune reactions involved in the development of destructive processes in the pulmonary parenchyma. Regarding NK1-positive elements, it should be noted that there is no change in their content in the lung tissue and a moderate increase in the density in the bronchial wall against the background of a decrease in the total number and NK1-immunoreactive tissue basophils. Obviously, substance P plays a key role in the implementation of neurogenic inflammation processes in chronic exposure to tobacco smoke. The established pattern of changes in NK1-positive structures can be explained by the ability of SP to cause mast cell degranulation and NK1 receptordependent release of histamine and serotonin involved in local inflammatory answer.

*Distribution of SP- and NK1-reactive structures in the bronchopulmonary system of rats. Coloring: immunoperoxidase reaction on SP; repainting, hematoxylin-eosin. Scale: A, 100 microns; B–E, 50 microns.* *Morphometric characteristics of SP- and NK1-immunoreactive structures in the bronchopulmonary system of rats.*

One of the leading stimulators of the synthesis of substance P in the model of long-term tobacco smoking is hypoxia which changes the humoral regulation of blood flow [55]. SP can adjust the change in vessel diameter at the unchanged vascular wall using an axon reflex for adequate blood flow at a given point in time. However, when the architectonics of the vascular wall changes, the SP loses its function as a regulator and can participate in both excessive vasodilation and paradoxical vasoconstriction.

In the development of the structural remodeling of the respiratory system, there are several morphological phenomena that accompany this process and are the basis for the development of reversible and irreversible morphofunctional changes. These include thinning of the epithelial layer, development of subepithelial fibrosis, an increase in smooth muscle thickness, an increase in the number and/or size of the submucosal glands, and the activation of angiogenesis processes [56]. In the pathogenesis of the changes taking place, great importance is attached to the activity of the enzymes of the extracellular matrix, which ensure the degradation of its interstitial proteins. Modern advances in proteomics have shown that for normal development, physiological renewal, restoration of healthy tissues, and the formation of pathological changes in tissue morphology, two groups of proteins are leading—MMPs and their tissue inhibitors [57, 58]. MMPs are a family of 20 zinc and calcium-dependent endopeptidases capable of cleaving almost all components of the extracellular matrix of connective tissues [59]. The level of synthesis and secretion of MMP into the extracellular space is regulated by transcription factors, and their proteolytic activity depends on the chemical transformations of the enzyme molecule in the interstitial space. As a result, either activation of the proenzymes or inhibition of their active forms can be observed. Depending on the type of protein metabolized, MMP can be divided into collagenases (MMP-1, MMP-8, and MMP-13), gelatinase (MMP-2 and MMP-9), stromalins (MMP-3 and MMP-10), etc. [60, 61]. In mammals there are four known TIMPs that inhibit all MMPs in a 1:1 ratio by strong covalent bonding [62]. It is believed that the balance of proteolytic and antiproteolytic mechanisms maintained in different tissues and organs is carried out by a specific set of intercellular matrix enzymes and their inhibitors [59, 63]. On the other hand, each process has a specific set of depressed matrix proteolytic enzymes. In this regard, great prospects in creating targeted therapy for many pathological processes are associated with the determination of the tissue specificity of the enzymes of the extracellular matrix and the identification of patterns of changes in their activity during the development of pathology.

#### **Figure 3.**

*Immunohistochemical (A–C) and biochemical determination of MMP in the bronchopulmonary system of rats with a model of long-term tobacco smoking. Coloring—immunohistochemical reaction to MMP-2 and MMP-9. Scale: A, B, B—50 μm. Localization of MMP-2 in the wall of the bronchus (A, B) and interalveolar septa (C). (D) Zymogram of MMP-2 and MMP-9. Lanes 1–4, lung homogenates of rats of the control group; lanes 5–8, lung homogenates of rats with a model of long-term tobacco smoking.*


#### **Table 4.**

*The contents of MMP-2 and MMP-9 in the homogenates of the lungs of rats.*

A number of studies have shown the role of individual types of MMP in the development of nicotine-associated pathology of the lungs and bronchi [57, 58]. To clarify the role of the leading MMP—MMP9 related to the inducible form and MMP2—considered as a constitutive variant of the enzyme in the development of pulmonary emphysema associated with long-term smoking, we studied the immunohistochemical and biochemical content of enzymes in the tissues and homogenates of rats with long-term smoking patterns (**Figure 3**).

In the bronchopulmonary system of rats, prolonged exposure to tobacco smoke is accompanied by ambiguous dynamics of the content of matrix metalloproteinases and their inhibitors. Normally, the activity of MMP-2 and MMP-9 is recorded in the cytoplasm and processes of bronchial and pulmonary fibroblasts, which form a thin MMP-positive strip in the lamina propria of the bronchial mucosa (**Figure 3A, B**) and in the interalveolar septa (**Figure 3C**). In the lungs and bronchi of rats with the long-term tobacco smoking model, a marked decrease in the immunohistochemical activity of MMP-2 and MMP-9 was observed. At the same time, in the acute phase of the experiment, the number and intensity of coloring of immunopositive structures on MMP-2 and MMP-9 are higher than in the control group. According to the quantitative

**25**

MMPs decreases evenly.

*model of prolonged smoking (indicated by arrows).*

**Figure 4.**

smoking (**Figure 4**).

**formation in humans**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

determination of enzymes in the homogenates of lung tissue (**Figure 3D**, **Table 4**), the resulting trend is confirmed. That is, with the development of pulmonary

*The distribution of the content of TIMP-2 in the lungs of rats of the control (A–C) and with the model of longterm tobacco smoking (D) groups. Coloring—immunohistochemical reaction to TIMP-2. Scale A, 100 microns; GD, 50 microns. A total enzyme content in the tissues of the bronchopulmonary system. B-TIMP-2-positive fibroblasts of the interalveolar septa. B-content of the enzyme in the epithelial cells of the small bronchus (indicated by arrows). G-reduction of the enzyme content in epithelial cells of the bronchus of rats with a* 

emphysema associated with prolonged smoking in the lung tissue, the content of both

An analysis of the immunohistochemical composition of the tissue inhibitor of both MMP and TIMP-2 showed a marked decrease in its representation in the structures of the bronchopulmonary system of animals on a model of long-term

In intact animals, the enzyme localization occurs in the respiratory epithelial cells of the bronchial membrane (**Figure 4C**, indicated by arrows) and fibroblasts of the interalveolar septa (**Figure 4B**). In animals of the main group, the overall intensity of immunohistochemical staining of lung tissue decreases, and at high magnifications of the microscope, it is possible to fix a significant depression of the color or complete disappearance of the enzyme content in the epithelial lining cells

According to the data obtained, the immunolocalization of MMP-2, MMP-9, and TIMP-2 repeats the basic pattern of distribution of pro-inflammatory cells and coincides with the foci of the most noticeable rearrangements of the connective tissue of the bronchi and the pulmonary parenchyma. In the acute phase of the experiment, the activity of the markers is significantly higher compared to the control; after 6 months of exposure to smoke, there is a decrease of the proteolytic

of the bronchi and lung parenchyma tissue (**Figure 4**, indicated by arrows).

**3.2 Study of the neurogenic inflammation mechanisms of the emphysema** 

In addition to studying the processes of neurogenic inflammation and the contribution of matrix metalloproteinases to the development of emphysema in the

activity and at the same time the processes of its inhibition.

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

#### **Figure 4.**

*Update in Respiratory Diseases*

**Figure 3.**

Conventional density units

*The differences are significant with р < 0.05.*

*\**

**Table 4.**

**24**

A number of studies have shown the role of individual types of MMP in the development of nicotine-associated pathology of the lungs and bronchi [57, 58]. To clarify the role of the leading MMP—MMP9 related to the inducible form and MMP2—considered as a constitutive variant of the enzyme in the development of pulmonary emphysema associated with long-term smoking, we studied the immunohistochemical and biochemical content of enzymes in the tissues and homog-

ММР-9/ММР-2 2.02 (control) 1.83 (experiment (long-term smoking

*Immunohistochemical (A–C) and biochemical determination of MMP in the bronchopulmonary system of rats with a model of long-term tobacco smoking. Coloring—immunohistochemical reaction to MMP-2 and MMP-9. Scale: A, B, B—50 μm. Localization of MMP-2 in the wall of the bronchus (A, B) and interalveolar septa (C). (D) Zymogram of MMP-2 and MMP-9. Lanes 1–4, lung homogenates of rats of the control group; lanes 5–8,* 

**term smoking model)**

**ММР-9 ММР-2**

742689.75 450081.25\* 367243.25 246414.75\*

**Control Experiment (long-term** 

model))

**smoking model)**

In the bronchopulmonary system of rats, prolonged exposure to tobacco smoke is accompanied by ambiguous dynamics of the content of matrix metalloproteinases and their inhibitors. Normally, the activity of MMP-2 and MMP-9 is recorded in the cytoplasm and processes of bronchial and pulmonary fibroblasts, which form a thin MMP-positive strip in the lamina propria of the bronchial mucosa (**Figure 3A, B**) and in the interalveolar septa (**Figure 3C**). In the lungs and bronchi of rats with the long-term tobacco smoking model, a marked decrease in the immunohistochemical activity of MMP-2 and MMP-9 was observed. At the same time, in the acute phase of the experiment, the number and intensity of coloring of immunopositive structures on MMP-2 and MMP-9 are higher than in the control group. According to the quantitative

enates of rats with long-term smoking patterns (**Figure 3**).

*The contents of MMP-2 and MMP-9 in the homogenates of the lungs of rats.*

*lung homogenates of rats with a model of long-term tobacco smoking.*

**Indicators Control Experiment (long-**

*The distribution of the content of TIMP-2 in the lungs of rats of the control (A–C) and with the model of longterm tobacco smoking (D) groups. Coloring—immunohistochemical reaction to TIMP-2. Scale A, 100 microns; GD, 50 microns. A total enzyme content in the tissues of the bronchopulmonary system. B-TIMP-2-positive fibroblasts of the interalveolar septa. B-content of the enzyme in the epithelial cells of the small bronchus (indicated by arrows). G-reduction of the enzyme content in epithelial cells of the bronchus of rats with a model of prolonged smoking (indicated by arrows).*

determination of enzymes in the homogenates of lung tissue (**Figure 3D**, **Table 4**), the resulting trend is confirmed. That is, with the development of pulmonary emphysema associated with prolonged smoking in the lung tissue, the content of both MMPs decreases evenly.

An analysis of the immunohistochemical composition of the tissue inhibitor of both MMP and TIMP-2 showed a marked decrease in its representation in the structures of the bronchopulmonary system of animals on a model of long-term smoking (**Figure 4**).

In intact animals, the enzyme localization occurs in the respiratory epithelial cells of the bronchial membrane (**Figure 4C**, indicated by arrows) and fibroblasts of the interalveolar septa (**Figure 4B**). In animals of the main group, the overall intensity of immunohistochemical staining of lung tissue decreases, and at high magnifications of the microscope, it is possible to fix a significant depression of the color or complete disappearance of the enzyme content in the epithelial lining cells of the bronchi and lung parenchyma tissue (**Figure 4**, indicated by arrows).

According to the data obtained, the immunolocalization of MMP-2, MMP-9, and TIMP-2 repeats the basic pattern of distribution of pro-inflammatory cells and coincides with the foci of the most noticeable rearrangements of the connective tissue of the bronchi and the pulmonary parenchyma. In the acute phase of the experiment, the activity of the markers is significantly higher compared to the control; after 6 months of exposure to smoke, there is a decrease of the proteolytic activity and at the same time the processes of its inhibition.

#### **3.2 Study of the neurogenic inflammation mechanisms of the emphysema formation in humans**

In addition to studying the processes of neurogenic inflammation and the contribution of matrix metalloproteinases to the development of emphysema in the

#### **Figure 5.**

*Distribution of the content of SP (A, C, E, G) and NK1 (B, D, F, H) in the bronchopulmonary system in persons with emphysema. Coloring: immunohistochemical reaction to SP and NK1, stained with hematoxylin. Scale: A, B, E, G (50 microns); C, D (100 microns); and F, H (20 microns). Nerve fibers innervating the wall of the bronchus (A) and interalveolar partitions (C). Localization of SP-positive macrophages in peribronchial infiltrates (E). SP-positive glandulocytes of the bronchial glands (G). Localization of neurokinin receptors on the surface of peribronchial macrophages (B), dust macrophages (D), vascular endothelial cells (F), and chondrocytes of the fibrocartilage membrane of the bronchi (H).*

experiment, we analyzed the content of neurokinin system markers, the localization, and the content of MMP-2, MMP-9, and TIMP-2 in human lung tissue structures. Morphological studies of autopsy material were performed on 12 individuals aged 51–65 years and 3 women and 9 men, average age 61.5 ± 4.14 years, who died a sudden death outside the hospital. The long-term history of tobacco smoking was clarified from the close relatives and on the basis of the data of the outpatient card. Features of the distribution and activity of SP, NK1, MMP-9, and TIMP-2, in lung tissues were investigated using the immunoperoxidase method on cryostat sections

**27**

**Figure 7.**

**Figure 6.**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

of 15 μm in thickness according to the standard procedure using the primary

In lung tissue and bronchial wall of patients with pulmonary emphysema, positive SP immunoreactivity is found mainly in the nerve fibers (**Figure 5**). More common are single conductors having a uniform ribbonlike course and numerous varicose thickenings. With a successful coincidence of the cut plane with the spatial geometry of the fibers, it is possible to observe beams extending 300–500 μm. Fibers penetrate through the walls of the bronchi of medium and small caliber, spread around the perimeter of the submucosa (**Figure 5A**, **B**). In the interstitial tissue, lightweight fibers have a diameter of 0.5–1 microns, and sometimes they are grouped into clusters with the formation of numerous terminals. Probably, the latter are areas of the most dense accumulation of neuromuscular and glandular contacts. The morphological characteristics of the colored conductors allow them to be treated as mixed (afferent and motor) fibers. High SP expression is also detected in peribronchial leukocyte infiltrates (**Figure 5D**). Here, high immunoreactivity is observed for neurokinin receptors of type 1 (**Figure 5B, D**). The preferential localization of the NK1 surface of the membranes of the secretory epithelial cells of the bronchial glands, alveolar and stromal macrophages, microvascular endothelial cells, and elements of the fibrocartilage membrane (**Figure 5B, D, E, H**) should be emphasized. Prolonged pathological effects of tobacco combustion products entail the formation of structural changes with the active involvement of the neurokinin innervation apparatus localized in the mucous membranes of the respiratory system. The increase in the number of macrophage cells and NK1-positive macrophages, and the direct interaction between them and afferent fibers, through terminals, suggests the involvement of sensory nerve fibers in the regulation of local immune,

*Localization of MMP-9 in the lungs (A, B) of a person. Coloring: immunohistochemical reaction to MMP-9,* 

*Localization of TIMP-2 pulmonary parenchyma in individuals with emphysema. Coloring: immunohistochemical reaction to TIMP-2, stained with hematoxylin. Scale: 100 microns.*

*stained with hematoxylin. Scale: A (50 microns); B (100 microns).*

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

antibody line described above.

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

of 15 μm in thickness according to the standard procedure using the primary antibody line described above.

In lung tissue and bronchial wall of patients with pulmonary emphysema, positive SP immunoreactivity is found mainly in the nerve fibers (**Figure 5**). More common are single conductors having a uniform ribbonlike course and numerous varicose thickenings. With a successful coincidence of the cut plane with the spatial geometry of the fibers, it is possible to observe beams extending 300–500 μm. Fibers penetrate through the walls of the bronchi of medium and small caliber, spread around the perimeter of the submucosa (**Figure 5A**, **B**). In the interstitial tissue, lightweight fibers have a diameter of 0.5–1 microns, and sometimes they are grouped into clusters with the formation of numerous terminals. Probably, the latter are areas of the most dense accumulation of neuromuscular and glandular contacts. The morphological characteristics of the colored conductors allow them to be treated as mixed (afferent and motor) fibers. High SP expression is also detected in peribronchial leukocyte infiltrates (**Figure 5D**). Here, high immunoreactivity is observed for neurokinin receptors of type 1 (**Figure 5B, D**). The preferential localization of the NK1 surface of the membranes of the secretory epithelial cells of the bronchial glands, alveolar and stromal macrophages, microvascular endothelial cells, and elements of the fibrocartilage membrane (**Figure 5B, D, E, H**) should be emphasized.

Prolonged pathological effects of tobacco combustion products entail the formation of structural changes with the active involvement of the neurokinin innervation apparatus localized in the mucous membranes of the respiratory system. The increase in the number of macrophage cells and NK1-positive macrophages, and the direct interaction between them and afferent fibers, through terminals, suggests the involvement of sensory nerve fibers in the regulation of local immune,

#### **Figure 6.**

*Update in Respiratory Diseases*

**26**

**Figure 5.**

experiment, we analyzed the content of neurokinin system markers, the localization, and the content of MMP-2, MMP-9, and TIMP-2 in human lung tissue structures. Morphological studies of autopsy material were performed on 12 individuals aged 51–65 years and 3 women and 9 men, average age 61.5 ± 4.14 years, who died a sudden death outside the hospital. The long-term history of tobacco smoking was clarified from the close relatives and on the basis of the data of the outpatient card. Features of the distribution and activity of SP, NK1, MMP-9, and TIMP-2, in lung tissues were investigated using the immunoperoxidase method on cryostat sections

*(F), and chondrocytes of the fibrocartilage membrane of the bronchi (H).*

*Distribution of the content of SP (A, C, E, G) and NK1 (B, D, F, H) in the bronchopulmonary system in persons with emphysema. Coloring: immunohistochemical reaction to SP and NK1, stained with hematoxylin. Scale: A, B, E, G (50 microns); C, D (100 microns); and F, H (20 microns). Nerve fibers innervating the wall of the bronchus (A) and interalveolar partitions (C). Localization of SP-positive macrophages in peribronchial infiltrates (E). SP-positive glandulocytes of the bronchial glands (G). Localization of neurokinin receptors on the surface of peribronchial macrophages (B), dust macrophages (D), vascular endothelial cells* 

*Localization of MMP-9 in the lungs (A, B) of a person. Coloring: immunohistochemical reaction to MMP-9, stained with hematoxylin. Scale: A (50 microns); B (100 microns).*

#### **Figure 7.**

*Localization of TIMP-2 pulmonary parenchyma in individuals with emphysema. Coloring: immunohistochemical reaction to TIMP-2, stained with hematoxylin. Scale: 100 microns.*

inflammatory, and destructive processes in the lung tissue during smoking-induced emphysema.

In contrast to the experimental data, in individuals with long periods of smoking and emphysema, there is an increase in the immunohistochemical density of MMP-9 in the pulmonary parenchyma (**Figure 6**), while TIMP-2 is practically undetermined (**Figure 7**).

In this way, from the presented data of experimental modeling of emphysema associated with long-term smoking, as well as studies in people with pulmonary emphysema and long-term tobacco smoking experience, neurogenic inflammation takes an active part in the processes of remodeling of lung tissue. Markers of neuro-mediated inflammation activity are overexpression of SP-containing nerve fibers, the presence of NK-1-tagged macrophages, mast cell degranulation, and an immune-mediated pattern of inflammatory infiltrate. Pathomorphosis of pulmonary parenchyma destruction in nicotine-associated pulmonary emphysema is associated with dysregulation in the state of the family of matrix metalloproteinases. In the acute period of exposure to tobacco combustion products, overexpression of MMP-9 is observed with suppression of the activity of the tissue inhibitor TIMP-2, followed by depression of the tissue content of both MMP-2 and MMP-9 and an inhibitor of their activity TIMP-2. In individuals with pulmonary emphysema, the MMP-9 tissue pattern retains its excessive representation.

#### **4. Conclusions and future directions**

Results from human and animal studies indicate that endothelial dysfunction and injury contribute not only to the genesis and progression of pulmonary lesions in COPD (especially emphysema development) but may also contribute to some of the common comorbidities and systemic effects reported in COPD patients. Vascular endothelium initiates and modulates the main pathomorphic processes in COPD and smoking. In particular, endothelium activation is an important factor of initiation, development and persistence of inflammation, and vessel and tissue remodeling, in particular emphysema. It is not by chance that the relationship of emphysema of the lungs is described in violation of the mechanical properties of the aorta and excessive stiffness of other exponents' bloodstream [4, 6, 64]. At the basis of these pathological processes are common (genetically determined and pathologically determined) mechanisms associated with impaired collagen-elastin metabolism.

The latest studies are conducted in the direction of studying not simple, associated with the endothelium, but specific neuro-mediated mechanisms of emphysema development in COPD and smoking. Our studies presented in this chapter describe the study of the processes of neurogenic inflammation and the contribution of matrix metalloproteinases to the development of emphysema in the experiment and in humans.

We are confident that there is a special morphofunctional continuum in the development of lower respiratory tract remodeling in response to chronic exposure to tobacco smoke and the development of inflammation in COPD. New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. Future studies should also assess the extent to which endothelial dysfunction and injury, particularly neuro-mediated mechanisms, underlie emphysema in COPD and smoking as target to therapeutic and prophylactic impacts.

**29**

**Author details**

provided the original work is properly cited.

Vera Nevzorova, Tatiana Brodskaya\* and Eugeny Gilifanov Pacific State Medical University, Vladivostok, Russia

\*Address all correspondence to: brodskaya@mail.ru

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms*

*DOI: http://dx.doi.org/10.5772/intechopen.85927*

No any conflict of interests.

**Acronyms and abbreviations**

VEGFR VEGF receptor NO Nitric oxide ET-1 Endothelinum-1

SP Substance P

COPD Chronic obstructive pulmonary disease VEGF Vascular endothelial growth factor

VEGF Vascular endothelial growth factor

ММP Matrix metalloproteinases

sPECAM-1 Soluble platelet endothelial cell adhesion molecule

**Conflict of interest**

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

## **Conflict of interest**

*Update in Respiratory Diseases*

undetermined (**Figure 7**).

emphysema.

inflammatory, and destructive processes in the lung tissue during smoking-induced

In contrast to the experimental data, in individuals with long periods of smoking and emphysema, there is an increase in the immunohistochemical density of MMP-9 in the pulmonary parenchyma (**Figure 6**), while TIMP-2 is practically

In this way, from the presented data of experimental modeling of emphysema associated with long-term smoking, as well as studies in people with pulmonary emphysema and long-term tobacco smoking experience, neurogenic inflammation takes an active part in the processes of remodeling of lung tissue. Markers of neuro-mediated inflammation activity are overexpression of SP-containing nerve fibers, the presence of NK-1-tagged macrophages, mast cell degranulation, and an immune-mediated pattern of inflammatory infiltrate. Pathomorphosis of pulmonary parenchyma destruction in nicotine-associated pulmonary emphysema is associated with dysregulation in the state of the family of matrix metalloproteinases. In the acute period of exposure to tobacco combustion products, overexpression of MMP-9 is observed with suppression of the activity of the tissue inhibitor TIMP-2, followed by depression of the tissue content of both MMP-2 and MMP-9 and an inhibitor of their activity TIMP-2. In individuals with pulmonary emphy-

sema, the MMP-9 tissue pattern retains its excessive representation.

Results from human and animal studies indicate that endothelial dysfunction and injury contribute not only to the genesis and progression of pulmonary lesions in COPD (especially emphysema development) but may also contribute to some of the common comorbidities and systemic effects reported in COPD patients. Vascular endothelium initiates and modulates the main pathomorphic processes in COPD and smoking. In particular, endothelium activation is an important factor of initiation, development and persistence of inflammation, and vessel and tissue remodeling, in particular emphysema. It is not by chance that the relationship of emphysema of the lungs is described in violation of the mechanical properties of the aorta and excessive stiffness of other exponents' bloodstream [4, 6, 64]. At the basis of these pathological processes are common (genetically determined and pathologically determined) mechanisms associated with impaired collagen-elastin metabolism. The latest studies are conducted in the direction of studying not simple, associated with the endothelium, but specific neuro-mediated mechanisms of emphysema development in COPD and smoking. Our studies presented in this chapter describe the study of the processes of neurogenic inflammation and the contribution of matrix metalloproteinases to the development of emphysema in the

We are confident that there is a special morphofunctional continuum in the development of lower respiratory tract remodeling in response to chronic exposure to tobacco smoke and the development of inflammation in COPD. New data suggest that imbalance of neuro-mediated interactions, alteration of vasomotoric signaling mechanisms, secretion, mucociliary clearance, cytoprotection involving substance P-dependent components with impaired content, and development of dystopia of matrix metalloproteinases and their tissue inhibitors are involved in the initiation of morphological restructuring. Future studies should also assess the extent to which endothelial dysfunction and injury, particularly neuro-mediated mechanisms, underlie emphysema in COPD and smoking as target to therapeutic and prophylac-

**4. Conclusions and future directions**

experiment and in humans.

**28**

tic impacts.

No any conflict of interests.

## **Acronyms and abbreviations**


## **Author details**

Vera Nevzorova, Tatiana Brodskaya\* and Eugeny Gilifanov Pacific State Medical University, Vladivostok, Russia

\*Address all correspondence to: brodskaya@mail.ru

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Global Initiative for Chronic Obstructive Pulmonary Disease [Internet]. 2018. Available from: http:// www.goldcopd.org

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[13] Vukic DA, Ruzic A, Samarzija M, et al. Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease. Medical Hypotheses. 2015;**84**:155-158. DOI: 10.1016/ S2213-2600(17)30236-9

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737-744. DOI: 10.1164/ ajrccm.163.3.2002117

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*DOI: http://dx.doi.org/10.5772/intechopen.85927*

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[17] Huertas A, Guignabert C, Barberà JA, Bärtsch P, Bhattacharya J, et al. Pulmonary vascular endothelium: The orchestra conductor in respiratory diseases: Highlights from basic research to therapy. The European Respiratory Journal. 2018;**51**(4):1700745. DOI: 10.1183/13993003.00745-2017. PMID:

[18] Letsiou E, Bauer N. Endothelial extracellular vesicles in pulmonary function and disease. Current Topics in Membranes. 2018;**82**:197-256. DOI: 10.1016/bs.ctm.2018.09.002. PMID:

[19] Green CE, Turner AM. The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD). Respiratory Research. 2017;**18**(1):20. DOI: 10.1186/s12931-017-0505-1. PMID:

[20] García-Lucio J, Peinado VI, de Jover L, Del Pozo R, Blanco I, et al. Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease. PLoS One. 2018;**13**(4):e0195724. DOI: 10.1371/ journal.pone.0195724. PMID: 29672621

[21] Lu Q, Gottlieb E, Rounds S. Effects of cigarette smoke on pulmonary endothelial cells. American Journal of Physiology Lung Cellular and Molecular Physiology. 2018;**314**(5):L743-L756. DOI: 10.1152/ajplung.00373.2017. PMID:

JCI10259

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29545281

30360780

8100233

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Inhibition of VEGF receptors causes lung cell apoptosis and emphysema. The Journal of Clinical Investigation. 2000;**106**:1311-1319. DOI: 10.1172/ JCI10259

[16] Voelkel NF, Cool CD. Pulmonary vascular involvement in chronic obstructive pulmonary disease. The European Respiratory Journal Supplement. 2003;**46**:28s-32s. DOI: 10.1183/09031936.03.00000503. PMID: 14621104

[17] Huertas A, Guignabert C, Barberà JA, Bärtsch P, Bhattacharya J, et al. Pulmonary vascular endothelium: The orchestra conductor in respiratory diseases: Highlights from basic research to therapy. The European Respiratory Journal. 2018;**51**(4):1700745. DOI: 10.1183/13993003.00745-2017. PMID: 29545281

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[19] Green CE, Turner AM. The role of the endothelium in asthma and chronic obstructive pulmonary disease (COPD). Respiratory Research. 2017;**18**(1):20. DOI: 10.1186/s12931-017-0505-1. PMID: 8100233

[20] García-Lucio J, Peinado VI, de Jover L, Del Pozo R, Blanco I, et al. Imbalance between endothelial damage and repair capacity in chronic obstructive pulmonary disease. PLoS One. 2018;**13**(4):e0195724. DOI: 10.1371/ journal.pone.0195724. PMID: 29672621

[21] Lu Q, Gottlieb E, Rounds S. Effects of cigarette smoke on pulmonary endothelial cells. American Journal of Physiology Lung Cellular and Molecular Physiology. 2018;**314**(5):L743-L756. DOI: 10.1152/ajplung.00373.2017. PMID: 29351435

[22] Cui M, Cui R, Liu K, Dong JY, Imano H, et al. Associations of tobacco smoking with impaired endothelial function: The circulatory risk in communities study (CIRCS). Journal of Atherosclerosis and Thrombosis. 2018;**25**(9):836-845. DOI: 10.5551/ jat.42150. PMID: 29415955

[23] Skurikhin EG, Krupin VA, Pershina OV, Pan ES, Ermolaeva LA, et al. Endothelial progenitor cells and Notch-1 signaling as markers of alveolar endothelium regeneration in pulmonary emphysema. Bulletin of Experimental Biology and Medicine. 2018;**166**(2): 201-206. DOI: 10.1007/s10517-018-4314-4. PMID: 30488216

[24] Truong TM, Li H, Dhapare S, Desai UR, Voelkel NF, Sakagami M. Sulfated dehydropolymer of caffeic acid: In vitro anti-lung cell death activity and in vivo intervention in emphysema induced by VEGF receptor blockade. Pulmonary Pharmacology & Therapeutics. 2017;**45**:181-190. DOI: 10.1016/j. pupt.2017.06.007

[25] Tuder RM, Zhen L, Cho CY, et al. Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade. American Journal of Respiratory Cell and Molecular Biology. 2003;**29**(1):88-97. DOI: 10.1165/ rcmb.2002-0228OC

[26] Kasahara Y, Tuder RM, Cool CD, et al. Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. American Journal of Respiratory and Critical Care Medicine. 2001;**163**: 737-744. DOI: 10.1164/ ajrccm.163.3.2002117

[27] Yasuo M, Mizuno S, Kraskauskas D, et al. Hypoxia inducible factor-1alpha in human emphysema lung tissue. The European Respiratory

**30**

pnas.0913880107

*Update in Respiratory Diseases*

[1] Global Initiative for Chronic Obstructive Pulmonary Disease [Internet]. 2018. Available from: http://

[2] Woodruff PG, Barr RG, Bleecker E, et al. Clinical significance of symptoms in smokers with preserved pulmonary function. The New England Journal of Medicine. 2016;**374**(19):1811-1821. DOI: [8] Iyer KS, Newell JD Jr, Jin D, et al. Quantitative dual-energy computed tomography supports a vascular etiology of smoking-induced inflammatory lung disease. American Journal of Respiratory and Critical Care Medicine. 2016;**193**(6):652-661. DOI: 10.1164/

[9] Peinado VI, Pizarro S, Barbera JA. Pulmonary vascular involvement in COPD. Chest. 2008;**134**(4):808-814.

[10] Brodskaya ТA, Nevzorova VA, Geltser BI, Motkina EV. Endothelial dysfunction and respiratory disease. Terapevticheskij Arkhiv. 2007;**79**(3):

[11] Polverino BR, Celli CA. Owen COPD as an endothelial disorder: Endothelial injury linking lesions in the lungs and other organs? Pulmonary Circulation. 2018;**8**(1):2045894018758528. DOI: 10.1177/2045894018758528. PMID:

[12] Moro L, Pedone C, Scarlata S, et al. Endothelial dysfunction in chronic obstructive pulmonary disease. Angiology. 2008;**59**:357-364. DOI: 10.1177/0003319707306141

[13] Vukic DA, Ruzic A, Samarzija M, et al. Persistent endothelial dysfunction turns the frequent exacerbator COPD from respiratory disorder into a progressive pulmonary and systemic vascular disease. Medical Hypotheses.

2015;**84**:155-158. DOI: 10.1016/ S2213-2600(17)30236-9

rccm.201706-1123LE

[15] Kasahara Y, Tuder RM, Taraseviciene-Stewart L, et al.

[14] Voelkel NF. Cigarette smoke is an endothelial cell toxin. American Journal of Respiratory and Critical Care Medicine. 2018;**197**:274. DOI: 10.1164/

DOI: 10.1378/chest.08-0820

76-84. PMID: 17526203

29468936

rccm.201506-1196OC

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www.goldcopd.org

10.1056/NEJMoa1505971

jamainternmed.2015.2735

[4] Nevzorova V, Brodskaya T,

Zakharchuk N. Smocking, respiratory diseases and endothelial dysfunction. In: Lenasi H, editor. Endothelial Dysfunction: Old Concepts and New Challenges. London: IntechOpen; 2018. pp. 307-326. ISBN 978-953-51-5698-7. DOI: 10.5772/intechopen.73555

[5] Sakao S, Voelkel NF, Tatsumi K. The vascular bed in COPD: Pulmonary hypertension and pulmonary vascular alterations. European Respiratory Review. 2014;**23**(133):350-355. DOI: 10.1007/978-3-662-47178-4\_14

[6] Brodskaya TA, Geltser BI, Nevzorova VA. Arterial Stiffness and Respiratory

Mechanisms and Clinical Significance). Vladivostok: Dalnauka; 2008. 248 p.

[7] Alford SK, van Beek EJ, McLennan G, Hoffman EA. Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers. Proceedings of the National Academy of Sciences of the United States of America. 2010;**107**(16):7485-7490. DOI: 10.1073/

Deseases (Pathophysiological

ISBN 978-5-8044-0928-0

[3] Regan EA, Lynch DA, Curran-Everett D, et al. Clinical and radiologic disease in smokers with normal spirometry. JAMA Internal Medicine. 2015;**175**(9):1539-1549. DOI: 10.1001/

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Journal of Respiratory Cell and

DOI: 10.1165/ajrcmb.25.3.4557

10.1164/ajrccm.163.7.2009041

[44] de Swert KO, Bracke KR, Demoor T, et al. Role of the tachykinin NK1 receptor in a murine model of cigarette smokeinduced pulmonary inflammation. Respiratory Research. 2009;**10**:37. DOI:

10.1186/1465-9921-10-37

[45] Xu J, Xu F. Lin Y Cigarette smoke synergizes lipopolysaccharide-induced interleukin-1β and tumor necrosis factor-α secretion from macrophages via substance P-mediated nuclear factor-κB

activation. American Journal of

[46] Xu J, Xu F, Wang R, Seagrave J, Lin Y, March TH. Cigarette smokeinduced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs. Experimental Lung Research. 2007;**33**(5):197-215. DOI: 10.1080/01902140701459514.

[47] Schelfhout V, Louis R, Lenz W, et al. The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma. Pulmonary Pharmacology & Therapeutics. 2006;**19**(6):413-418. DOI: 10.1016/j. pupt.2005.10.007. PMID: 16364669

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responsiveness in guinea pigs. American

Molecular Biology. 2001;**25**(3):299-305.

[43] Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2001;**163**(7):1693-1722. DOI:

*Smoking and COPD: Endothelium-Related and Neuro-mediated Emphysema Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.85927*

Journal. 2005;**26**(2):204-213. DOI: 10.1183/09031936.05.00095204

*Update in Respiratory Diseases*

jamcollsurg.2004.08.010

PMID: 15978458

pats.200603-047ms

[29] Takagi H, Umemoto TJ. How cigarette smoke accelerates abdominal aortic aneurysm. American College of Surgeons. 2005;**201**(1):149-150. DOI: 10.1016/j.jamcollsurg.2005.03.011.

[30] Lee JH. Decreased number of circulating endothelial progenitor cells in patients with emphysema. Proceedings of the American Thoracic Society. 2006;**3**:545-545. DOI: 10.1513/

[31] Borgas D, Chambers E, Newton J, et al. Cigarette smoke disrupted lung endothelial barrier integrity and increased susceptibility to acute lung injury via histone deacetylase 6. American Journal of Respiratory Cell and Molecular Biology. 2016;**54**:683- 696. DOI: 10.1165/rcmb.2015-0149OC

[32] U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease: The Biology and

Disease, A Report of the Surgeon General. Rockville, MD: Office of the Surgeon General; 2010. 792 p. ISBN 978- 0-16-084078-4. ISBN 10: 0160840783

[33] Patacchini R, Maggi CA. Tachykinins and neurogenic inflammation at visceral level.

S1567-7443(08)10413-6

Behavioral Basis of Smoking-Attributable

Neurogenic Inflammation in Health and Disease. 2009;**8**:289-320. DOI: 10.1016/

[34] Boschetto P, Miotto D, Bononi I, et al. Sputum substance P and

Journal. 2011;**37**:775-783. DOI: 10.1183/09031936.00022910

[28] Buckley C, Wyble CW, Borhani M, et al. Accelerated enlargement of experimental abdominal aortic aneurysms in a mouse model of chronic cigarette smoke exposure. Journal of the American College of Surgeons. 2004;**199**(6):896-903. DOI: 10.1016/j.

neurokinin A are reduced during exacerbations of chronic obstructive pulmonary disease. Pharmacology & Therapeutics. 2005;**18**(3):199-205. DOI: 10.1016/j.pupt.2004.12.006. PMID:

[35] De Swert KO, Bracke KR, Demoor T, Brusselle GG, Joos GF. Role of the tachykinin NK1 receptor in a murine model of cigarette smoke-induced pulmonary inflammation. Respiratory Research. 2004;**10**(1):37.1-37.3712. DOI:

10.1186/1465-9921-10-37

[36] Almeida TA, Rojo J, Nieto PM, et al. Tachykinins and tachykinin receptors: Structure and activity relationships. Current Medicinal Chemistry. 2004;**11**(15):2045-2081. DOI: 10.2174/0929867043364748

[37] Canning BJ, Spina D. Sensory nerves and airway irritability. Handbook of Experimental Pharmacology. 2009;**194**(194):139-183. DOI: 10.1007/978-3-540-79090-7\_5

[38] Joos GF, O'Connor B, Anderson SD, et al. Indirect airway challenges. The European Respiratory Journal. 2003;**21**(6):1050-1068. DOI: 10.1183/09031936.03.00008403

[39] Mapp CE, Miotto D, Braccioni F, et al. The distribution of neurokinin-1 and neurokinin-2 receptors in human central airways. American Journal of Respiratory and Critical Care Medicine.

2000;**161**:207-215. DOI: 10.1007/

the understanding of sensory neuropeptides. European Journal of Pharmacology. 2006;**533**(1-3):171-181. DOI: 10.1016/j.ejphar.2005.12.066

[41] D'hulst AI, Vermaelen KY, Brusselle GG, et al. Time course of cigarette smoke-induced pulmonary inflammation in mice. The European Respiratory

[40] de Swert KO, Joos GF. Extending

s11882-001-0081-8

15707854

**32**

[42] Kwong KL, Wu ZX, Kashon ML, et al. Chronic smoking enhances tachykinin synthesis and airway responsiveness in guinea pigs. American Journal of Respiratory Cell and Molecular Biology. 2001;**25**(3):299-305. DOI: 10.1165/ajrcmb.25.3.4557

[43] Kharitonov SA, Barnes PJ. Exhaled markers of pulmonary disease. American Journal of Respiratory and Critical Care Medicine. 2001;**163**(7):1693-1722. DOI: 10.1164/ajrccm.163.7.2009041

[44] de Swert KO, Bracke KR, Demoor T, et al. Role of the tachykinin NK1 receptor in a murine model of cigarette smokeinduced pulmonary inflammation. Respiratory Research. 2009;**10**:37. DOI: 10.1186/1465-9921-10-37

[45] Xu J, Xu F. Lin Y Cigarette smoke synergizes lipopolysaccharide-induced interleukin-1β and tumor necrosis factor-α secretion from macrophages via substance P-mediated nuclear factor-κB activation. American Journal of Respiratory Cell and Molecular Biology. 2011;**44**(3):302-308. DOI: 10.1165/ rcmb.2009-0288OC. PMID: 20160043

[46] Xu J, Xu F, Wang R, Seagrave J, Lin Y, March TH. Cigarette smokeinduced hypercapnic emphysema in C3H mice is associated with increases of macrophage metalloelastase and substance P in the lungs. Experimental Lung Research. 2007;**33**(5):197-215. DOI: 10.1080/01902140701459514. PMID: 17620183

[47] Schelfhout V, Louis R, Lenz W, et al. The triple neurokinin-receptor antagonist CS-003 inhibits neurokinin A-induced bronchoconstriction in patients with asthma. Pulmonary Pharmacology & Therapeutics. 2006;**19**(6):413-418. DOI: 10.1016/j. pupt.2005.10.007. PMID: 16364669

[48] Tai CF, Baraniuk JN. Upper airway neurogenic mechanisms. Current Opinion in Allergy and Clinical Immunology. 2002;**2**(1):11-19. DOI: 10.1097/00130832-200202000-00003

[49] Groneberg DA, Heppt W, Cryer A, et al. Toxic rhinitis-induced changes of human nasal mucosa innervation. Toxicologic Pathology. 2003;**31**(3):326- 331. DOI: 10.1080/01926230390204379

[50] Dinh QT, Klapp BF, Fischer A. Airway sensory nerve and tachykinins in asthma and COPD. Pneumologie. 2006;**60**(2):80-85. DOI: 10.1055/s-2005- 915587. PMID: 16463247

[51] Hens G, Raap U, Vanoirbeek J, et al. Selective nasal allergen provocation induces substance P-mediated bronchial hyperresponsiveness. American Journal of Respiratory Cell and Molecular Biology. 2011;**44**(4):517-523. DOI: 10.1165/rcmb.2009-0425OC

[52] Vergnolle N, Cenac N, Altier C, et al. A role for transient receptor potential vanilloid 4 in tonicityinduced neurogenic inflammation. British Journal of Pharmacology. 2010;**159**(5):1161-1173. DOI: 10.1007/ s00424-011-1071-x

[53] Zheng H, Liu Y, Huang T, et al. Development and characterization of a rat model of chronic obstructive pulmonary disease (COPD) induced by sidestream cigarette smoke. Toxicology Letters. 2009;**189**(3):225-234. DOI: 10.1016/j. toxlet.2009.06.850. PMID: 19524650

[54] Gilifanov EA, Nevzorova VA, Artyushkin SA, et al. Method for experimental modeling of inflammation in the paranasal sinuses in chronic tobacco smoking in rats. FSBEI HE TSMU Russia. - № 2012121065/14; Pat RU, 2522954, IPC G09B 23/28. - Bull. 2012; No. 20. pp. 1-8

[55] Lee LY, Pisarri TE. Afferent properties and reflex functions

of bronchopulmonary C-fibers. Respiration Physiology. 2001;**125**(1-2):47-65. DOI: 10.1016/ S0034-5687(00)00204-8

[56] Ramos-Barbón D, Suzuki M, Taha R, et al. Effect of alpha4-integrin blockade on CD4+ cell-driven late airway responses in the rat. American Journal of Respiratory and Critical Care Medicine. 2001;**163**(1):101-108. PMID: 11208633

[57] Nevzorova VA, Golotina OV, Shekunova OI, et al. Intracardiac and pulmonary hemodynamics and the state of the gas composition of blood with stable angina of stress associated with chronic obstructive pulmonary disease. Cardiovascular Therapy and Prevention. 2011;**10**(8):19-24

[58] Solovyova NI, Ryzhakova OS. Methods for determining the activity of matrix metalloproteinases. Kliniceskaja Laboratornaja Diagnostika. 2010;**16**:17-21

[59] Shoikhet YN, Korenovsky YV, Lepilov AV, et al. The role of matrix metalloproteinases in inflammatory diseases of the lungs. Problems of Clinical Medicine. 2008;**3**:99-101

[60] Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. American Journal of Respiratory Cell and Molecular Biology. 2003;**28**(1):12-24. DOI: 10.1165/ rcmb.2002-0166TR

[61] Ziora D, Dworniczak S, Kozielski J. Induced sputum metalloproteinases and their inhibitors in relation to exhaled nitrogen oxide and sputum nitric oxides and other inflammatory cytokines in patients with chronic obstructive pulmonary disease. Journal of Physiology and Pharmacology. 2008;**59**(6):809-817

[62] Lee WJ, Shin CY, Yoo BK, et al. Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharidestimulated primary astrocytes is mediated by extracellular signalregulated protein kinase 1/2 (Erk1/2). Glia. 2003;**41**(1):15-24. PMID: 12465042

[63] Sobolev GM, Sukhikh GT. The family of matrix metalloproteinases: General characteristics and physiological role. Obstetrics and Gynecology. 2007;**1**:5-8

[64] Brodskaya T, Nevzorova V, Zakharchuk N, Repina N. Aortic stiffness and polymorphisms of collagen-1 type 1a gene in COPD patients. Journal of Lung, Pulmonary and Respiratory Research. 2018;**5**(3): 81-85. DOI: 10.15406/ jlprr.2018.05.00167

**35**

**Chapter 3**

**Abstract**

and advanced age.

**1. Introduction**

Emphysema

Emphysema (Greek word meaning to inflate/to blow) is an increase in the size of airspace distal to the terminal bronchiolus, that is, hyperinflation of the alveoli due to the destruction of the gas-exchanging structures: alveolar walls, alveolar ducts, and respiratory bronchioles with coalescence of airspaces into the abnormal, much larger airspaces. The main consequences are the reduction of alveolar surface for gas exchange and the chronic obstructive pulmonary disease due to the destruction and disappearance of respiratory bronchioles with decreased total small airway diameter sum. Both decreased alveolar surface for gas exchange and chronic obstructive pulmonary disease lead to difficulty in breathing with dyspnea varying from mild to very severe. Two main pathohistologic types of emphysema are centriacinar and panacinar. Centriacinar emphysema involves the central portion of the acinus, and inflation mainly involves respiratory bronchioles and adjacent alveoli, and not all alveoli inside the acinus are involved. Panacinar (panlobular) emphysema is characterized by uniform enlargement and destruction of alveoli throughout the entire acinus. The panacinar emphysema is rare and its most common cause is hereditary alpha-1 antitrypsin deficiency. The centriacinar emphysema is the most frequent emphysema. It is mainly caused by smoking but also by coal dust exposure

**Keywords:** emphysema, chronic obstructive pulmonary disease, smoking, coal

Emphysema, enlarged airspaces due to destruction of alveolar walls, respiratory bronchioles, and alveolar ducts, is a well-defined disease. However, in the medical practice, it is mainly encountered as an essential component of the chronic obstructive pulmonary disease syndrome. Other components are chronic bronchitis, small airway disease, small airway hyperactivity, and inflammation. Chronic obstructive pulmonary disease presents with cough, sputum production, and exertional dyspnea. In advanced cases, patients are breathless while doing even simple daily activities and may develop resting hypoxemia (blue cyanotic lips and finger nails) that requires continuous application of supplemental oxygen. Chronic obstructive pulmonary disease during its course is complicated by viral, bacterial, and fungal infections, and pneumonias and chronic obstructive pulmonary disease are the fourth leading cause of death in the USA. Urban air pollution and industrial air pollution are contributory factors in the genesis of chronic obstructive pulmonary disease, and with increase in cigarette smoking in developing countries, an estimate is that the chronic obstructive pulmonary disease will rise from the sixth to the

dust, alpha-1 antitrypsin deficiency, oxidative radicals, telomeres

third most common cause of death worldwide by the year 2020 [1].

*Tomislav M. Jelic*

## **Chapter 3** Emphysema

*Tomislav M. Jelic*

## **Abstract**

*Update in Respiratory Diseases*

Respiration Physiology.

S0034-5687(00)00204-8

11208633

2011;**10**(8):19-24

2010;**16**:17-21

of bronchopulmonary C-fibers.

2001;**125**(1-2):47-65. DOI: 10.1016/

[57] Nevzorova VA, Golotina OV, Shekunova OI, et al. Intracardiac and pulmonary hemodynamics and the state of the gas composition of blood with stable angina of stress associated with chronic obstructive pulmonary disease. Cardiovascular Therapy and Prevention.

[58] Solovyova NI, Ryzhakova OS. Methods for determining the activity of matrix metalloproteinases. Kliniceskaja Laboratornaja Diagnostika.

[59] Shoikhet YN, Korenovsky YV, Lepilov AV, et al. The role of matrix metalloproteinases in inflammatory diseases of the lungs. Problems of Clinical Medicine. 2008;**3**:99-101

[60] Atkinson JJ, Senior RM. Matrix

metalloproteinase-9 in lung remodeling. American Journal of Respiratory Cell and Molecular Biology.

rcmb.2002-0166TR

2008;**59**(6):809-817

2003;**28**(1):12-24. DOI: 10.1165/

[61] Ziora D, Dworniczak S, Kozielski J. Induced sputum metalloproteinases and their inhibitors in relation to exhaled nitrogen oxide and sputum nitric oxides and other inflammatory cytokines in patients with chronic obstructive pulmonary disease. Journal of Physiology and Pharmacology.

[62] Lee WJ, Shin CY, Yoo BK, et al. Induction of matrix metalloproteinase-9

[56] Ramos-Barbón D, Suzuki M, Taha R, et al. Effect of alpha4-integrin blockade on CD4+ cell-driven late airway responses in the rat. American Journal of Respiratory and Critical Care Medicine. 2001;**163**(1):101-108. PMID:

(MMP-9) in lipopolysaccharidestimulated primary astrocytes is mediated by extracellular signalregulated protein kinase 1/2 (Erk1/2). Glia. 2003;**41**(1):15-24. PMID: 12465042

[63] Sobolev GM, Sukhikh GT. The family of matrix metalloproteinases:

General characteristics and physiological role. Obstetrics and

[64] Brodskaya T, Nevzorova V, Zakharchuk N, Repina N. Aortic stiffness and polymorphisms of collagen-1 type 1a gene in COPD patients. Journal of Lung, Pulmonary and Respiratory Research. 2018;**5**(3):

Gynecology. 2007;**1**:5-8

81-85. DOI: 10.15406/ jlprr.2018.05.00167

**34**

Emphysema (Greek word meaning to inflate/to blow) is an increase in the size of airspace distal to the terminal bronchiolus, that is, hyperinflation of the alveoli due to the destruction of the gas-exchanging structures: alveolar walls, alveolar ducts, and respiratory bronchioles with coalescence of airspaces into the abnormal, much larger airspaces. The main consequences are the reduction of alveolar surface for gas exchange and the chronic obstructive pulmonary disease due to the destruction and disappearance of respiratory bronchioles with decreased total small airway diameter sum. Both decreased alveolar surface for gas exchange and chronic obstructive pulmonary disease lead to difficulty in breathing with dyspnea varying from mild to very severe. Two main pathohistologic types of emphysema are centriacinar and panacinar. Centriacinar emphysema involves the central portion of the acinus, and inflation mainly involves respiratory bronchioles and adjacent alveoli, and not all alveoli inside the acinus are involved. Panacinar (panlobular) emphysema is characterized by uniform enlargement and destruction of alveoli throughout the entire acinus. The panacinar emphysema is rare and its most common cause is hereditary alpha-1 antitrypsin deficiency. The centriacinar emphysema is the most frequent emphysema. It is mainly caused by smoking but also by coal dust exposure and advanced age.

**Keywords:** emphysema, chronic obstructive pulmonary disease, smoking, coal dust, alpha-1 antitrypsin deficiency, oxidative radicals, telomeres

## **1. Introduction**

Emphysema, enlarged airspaces due to destruction of alveolar walls, respiratory bronchioles, and alveolar ducts, is a well-defined disease. However, in the medical practice, it is mainly encountered as an essential component of the chronic obstructive pulmonary disease syndrome. Other components are chronic bronchitis, small airway disease, small airway hyperactivity, and inflammation. Chronic obstructive pulmonary disease presents with cough, sputum production, and exertional dyspnea. In advanced cases, patients are breathless while doing even simple daily activities and may develop resting hypoxemia (blue cyanotic lips and finger nails) that requires continuous application of supplemental oxygen. Chronic obstructive pulmonary disease during its course is complicated by viral, bacterial, and fungal infections, and pneumonias and chronic obstructive pulmonary disease are the fourth leading cause of death in the USA. Urban air pollution and industrial air pollution are contributory factors in the genesis of chronic obstructive pulmonary disease, and with increase in cigarette smoking in developing countries, an estimate is that the chronic obstructive pulmonary disease will rise from the sixth to the third most common cause of death worldwide by the year 2020 [1].

## **2. Heading**

## **2.1 Morphologic and histologic features of the normal lung**

A normal lung consists of airways and alveoli. Airways are tubes (pipes) that conduct air to alveoli where gas exchange occurs. Oxygen (O2) through alveolar wall enters into red blood cells in the alveolar capillaries and binds to hemoglobin, while carbon dioxide (CO2) goes in opposite direction being released from hemoglobin, enters alveoli, and is being exhaled.

The trachea beyond the carina undergoes to about 23 generations of dichotomous branching. Airway tubes with diameter of more than 1 mm are called bronchi. With each division the diameter of the bronchus becomes smaller, but the sum of the two diameters exceeds diameter of the parent bronchus meaning that with divisions resistance to air flow becomes smaller. The bronchus consists of the lumen, mucosa, submucosa, muscularis, cartilage, and adventitia that is composed of connective tissue and contains lymphatics (**Figure 1**).

Bronchi are accompanied by branches of the pulmonary artery that have a diameter of similar size to the diameter of the bronchus they follow. The mucosa is mainly lined by columnar respiratory epithelium with cilia. All columnar cells lie on a basement membrane, but since columnar cells differ in their length, nuclei differ in their position regarding basal membrane, and respiratory epithelium appears stratified, but in fact it is pseudostratified. The mucosa also contains small number of mucinous cells that contain apical mucin, small number of basal cells, and rare neuroendocrine cells. Basal cells are precursors of ciliated cells and of mucinous goblet cells. Cilia arise from the apices of the respiratory cells and serve as escalator pushing mucin upstream to the throat and nose. Neuroendocrine cells are scattered singly and form small groups, neuroepithelial bodies near the airway bifurcations. The functional significance of the neuroendocrine cells is largely unknown. Beneath the pseudostratified ciliated mucosa is the submucosa that consists of loose connective tissue harboring bronchial mucous (seromucinous) glands, lymphoid tissue aggregates, and plasma cells. Mucinous glands secrete mucus composed of glycoprotein, proteoglycans, lipids, IgA (secretory) immunoglobulins, lysozyme peroxidase, and other substances to inactivate invading microorganisms, and trap air pollution particles. Cartilage plate and muscle bundles lie beneath the submucosa. The cartilage prevents collapse of the bronchial lumen. There are about 9–12 generations of bronchi. The smallest bronchi are 1 mm in diameter. Bronchi branch into the bronchiole. Bronchioles are less than 1 mm in diameter and they lack cartilage and

**37**

**Figure 3.**

**Figure 2.**

*Emphysema*

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

exocrine mucinous glands in their walls. The larger bronchioles are called terminal bronchioles and measure on average 0.5–1 mm. Since terminal bronchioles do not contain cartilage, they are also called membranous bronchioles (**Figure 2**). Terminal bronchioles consist of respiratory mucosa composed of one layer of cuboidal ciliated respiratory cells and occasional Clara cells. Clara cells are non-ciliated columnar epithelial cells with protuberant apical cytoplasm that contains granules of surfactant and protease inhibitors. Clara cells are also precursors of bronchiolar epithelial cells. Goblet cells are generally not present or rare in the mucosa of the terminal bronchioles. Beneath the mucosa of the terminal bronchiolus is a layer of smooth muscle and connective tissue adventitia. Terminal bronchioles branch into the respiratory bronchioles. One side of the airway wall of the respiratory bronchiolus is lined by simple columnar to cuboidal bronchiolar epithelium without cilia. The opposite wall is lined by alveoli, that is, the wall consists of openings of the alveolar sacs. The average diameter of respiratory bronchioles is 0.15–0.2 mm. The respiratory bronchioles branch into about two more generations of respiratory bronchioles. Respiratory bronchioles branch into alveolar ducts,

straight tubular spaces bounded entirely by alveoli (**Figure 3**).

In fact all alveoli (alveolar sacs) open into the alveolar ducts. Thus alveoli have incomplete wall and alveolar sacs are outpockets of alveolar ducts. Alveoli that appear lined with alveolar walls on all sides are in fact artifact of cut section. Alveolar ducts are not accompanied by the artery. The acinus is a functional unit of the lungs that consists of terminal bronchiolus with its respiratory bronchioles, alveolar ducts, and alveoli forming tridimensional spherical space with average

*Terminal bronchiolus, lined by respiratory epithelium, with no cartilage and no exocrine glands.*

*Alveolar duct and alveoli (original magnification* × *100) and alveolar septa with alveoli (original* 

*magnification* × *400). Courtesy of Dr. Nadia N. Naumova.*

#### *Emphysema DOI: http://dx.doi.org/10.5772/intechopen.83273*

*Update in Respiratory Diseases*

enters alveoli, and is being exhaled.

**2.1 Morphologic and histologic features of the normal lung**

connective tissue and contains lymphatics (**Figure 1**).

A normal lung consists of airways and alveoli. Airways are tubes (pipes) that conduct air to alveoli where gas exchange occurs. Oxygen (O2) through alveolar wall enters into red blood cells in the alveolar capillaries and binds to hemoglobin, while carbon dioxide (CO2) goes in opposite direction being released from hemoglobin,

The trachea beyond the carina undergoes to about 23 generations of dichotomous branching. Airway tubes with diameter of more than 1 mm are called bronchi. With each division the diameter of the bronchus becomes smaller, but the sum of the two diameters exceeds diameter of the parent bronchus meaning that with divisions resistance to air flow becomes smaller. The bronchus consists of the lumen, mucosa, submucosa, muscularis, cartilage, and adventitia that is composed of

Bronchi are accompanied by branches of the pulmonary artery that have a diameter of similar size to the diameter of the bronchus they follow. The mucosa is mainly lined by columnar respiratory epithelium with cilia. All columnar cells lie on a basement membrane, but since columnar cells differ in their length, nuclei differ in their position regarding basal membrane, and respiratory epithelium appears stratified, but in fact it is pseudostratified. The mucosa also contains small number of mucinous cells that contain apical mucin, small number of basal cells, and rare neuroendocrine cells. Basal cells are precursors of ciliated cells and of mucinous goblet cells. Cilia arise from the apices of the respiratory cells and serve as escalator pushing mucin upstream to the throat and nose. Neuroendocrine cells are scattered singly and form small groups, neuroepithelial bodies near the airway bifurcations. The functional significance of the neuroendocrine cells is largely unknown. Beneath the pseudostratified ciliated mucosa is the submucosa that consists of loose connective tissue harboring bronchial mucous (seromucinous) glands, lymphoid tissue aggregates, and plasma cells. Mucinous glands secrete mucus composed of glycoprotein, proteoglycans, lipids, IgA (secretory) immunoglobulins, lysozyme peroxidase, and other substances to inactivate invading microorganisms, and trap air pollution particles. Cartilage plate and muscle bundles lie beneath the submucosa. The cartilage prevents collapse of the bronchial lumen. There are about 9–12 generations of bronchi. The smallest bronchi are 1 mm in diameter. Bronchi branch into the bronchiole. Bronchioles are less than 1 mm in diameter and they lack cartilage and

*Portion of the wall of the bronchus with respiratory epithelium with cilia, smooth muscle layer, and cartilage.*

**2. Heading**

**36**

**Figure 1.**

exocrine mucinous glands in their walls. The larger bronchioles are called terminal bronchioles and measure on average 0.5–1 mm. Since terminal bronchioles do not contain cartilage, they are also called membranous bronchioles (**Figure 2**).

Terminal bronchioles consist of respiratory mucosa composed of one layer of cuboidal ciliated respiratory cells and occasional Clara cells. Clara cells are non-ciliated columnar epithelial cells with protuberant apical cytoplasm that contains granules of surfactant and protease inhibitors. Clara cells are also precursors of bronchiolar epithelial cells. Goblet cells are generally not present or rare in the mucosa of the terminal bronchioles. Beneath the mucosa of the terminal bronchiolus is a layer of smooth muscle and connective tissue adventitia. Terminal bronchioles branch into the respiratory bronchioles. One side of the airway wall of the respiratory bronchiolus is lined by simple columnar to cuboidal bronchiolar epithelium without cilia. The opposite wall is lined by alveoli, that is, the wall consists of openings of the alveolar sacs. The average diameter of respiratory bronchioles is 0.15–0.2 mm. The respiratory bronchioles branch into about two more generations of respiratory bronchioles. Respiratory bronchioles branch into alveolar ducts, straight tubular spaces bounded entirely by alveoli (**Figure 3**).

In fact all alveoli (alveolar sacs) open into the alveolar ducts. Thus alveoli have incomplete wall and alveolar sacs are outpockets of alveolar ducts. Alveoli that appear lined with alveolar walls on all sides are in fact artifact of cut section. Alveolar ducts are not accompanied by the artery. The acinus is a functional unit of the lungs that consists of terminal bronchiolus with its respiratory bronchioles, alveolar ducts, and alveoli forming tridimensional spherical space with average

#### **Figure 2.** *Terminal bronchiolus, lined by respiratory epithelium, with no cartilage and no exocrine glands.*

#### **Figure 3.**

*Alveolar duct and alveoli (original magnification* × *100) and alveolar septa with alveoli (original magnification* × *400). Courtesy of Dr. Nadia N. Naumova.*

diameter of 7.5 mm. There are about three generations of respiratory bronchioles inside the acinus and approximately 25,000 acini in normal adult male lungs with a volume of 5.25 liters [2]. Cluster of three to five terminal bronchioles, that is, acini, form pulmonary lobule. The pulmonary lobule is an anatomic unit, polygonal in shape, and bound by complete or incomplete connective tissue interlobular septa and measures about 1.5–3 cm.

Gas exchange starts in respiratory bronchioles and mainly occurs in alveoli. The alveolar wall (also called alveolar septum) is very thin in order to permit efficient gas exchange (**Figure 3**). It consists only of one layer of epithelial cells called pneumocytes. Pneumocytes type 1 are very thin, flat, large epithelial cells that cover 90% of the alveolar surface and are not capable of mitosis. Pneumocytes type 2 are cuboidal cell with large basal nucleus and prominent nucleolus. Pneumocytes type 2 secrete surfactant, are able to divide and participate in repair, and may become hyperplastic in response to alveolar damage. Pneumocytes type 2 are also precursors of pneumocytes type 1. Pneumocytes lie on the basal membrane that is fused with the basal membrane of the capillary endothelial cell. Thus the alveolar wall (septum) consists only of capillary sandwiched between the two layers of pneumocytes from two adjacent alveoli (**Figure 3**). An occasional myofibroblast may be present in the alveolar wall as well as rare scattered small lymphocytes, rare mesenchymal cells, and rare macrophages. Hematoxylin and eosin-stained sections of the normal lung on high magnification show delicate alveolar walls (septa) containing inconspicuous capillaries, occasional cuboidal cells of pneumocytes type 2, and nuclei of pneumocytes type 1, endothelial cell nuclei, and nuclei of rare scattered lymphocytes, mesenchymal cells, and macrophages. The cytoplasm of pneumocytes type 1 is too thin to be visible without special immunoperoxidase stains. Alveolar macrophages egress from capillaries, are increased in number in chronic inflammatory settings, and are involved in phagocytosis of foreign material as well in the inflammatory and immune responses.

The interstitium provides the connective tissue framework of the lungs and is composed of collagen fibers, elastic fibers, mesenchymal cells, and few inflammatory cells. In normal lungs the interstitium is generally inconspicuous and can be recognized only along bronchovascular bundles, around veins, and where it forms interlobular septa. In the children up to 4 years of age, the interstitium is more apparent and presents as thickening of the alveolar walls [3]. The term "small airways" includes airways with diameter of 2 mm and smaller and thus includes small bronchi, terminal bronchioles, and respiratory bronchioles.

#### **2.2 Morphologic and histologic features of emphysema**

Emphysema is permanent enlargement of airspaces distal to the terminal bronchiole (acinus) due to the destruction of the walls of the alveoli, alveolar ducts, and the respiratory bronchioles. Grossly, the lung is hyperinflated and spongy.

According to the location of the hyperinflated alveoli inside the acinus, there are four types of emphysema: centriacinar (centrilobular, proximal), panacinar (panlobular), distal acinar (paraseptal), and irregular (associated with scar). Each of the emphysema type has characteristic microscopic morphology and characteristic etiology.

The most frequent is centriacinar emphysema which comprises more than 95% of all emphysemas. **Centriacinar emphysema** involves proximal respiratory bronchiolus and adjacent alveoli, which is in the center of the acinus, hence the name centriacinar emphysema (**Figure 4**).

**39**

**Figure 5.**

*collagen fibers of interstitial (septal alveolar) fibrosis.*

*Emphysema*

**Figure 4.**

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

*Hematoxylin and eosin stain, original magnification 20×.*

matous (**Figures 4** and **5**).

Inhaled cigarette smoke or mineral dust, most frequently coal mine dust, reach respiratory bronchioles. There are no cilia in the respiratory bronchioles; cigarette smoke particles and coal dust particles (silica particles in the coal dust are the most toxic ones) stick there and initiate processes of inflammation and destruction. The first damaged structure is thus respiratory bronchiolus with its dilatation or disappearance. In the beginning, alveolar ducts and alveoli are spared. Soon their destruction and coalescence into the larger air space follows. In the acinus, which contains several (about 14) respiratory bronchioles, some bronchioles and alveoli are damaged, enlarged, and emphysematous, and some are not damaged and are normal in size. Thus characteristic microscopic feature with low power magnification of centroacinar emphysema is that some alveoli are normal and some emphyse-

*Centriacinar emphysema caused by coal mine dust. Some alveoli are normal, some emphysematous.* 

Cigarette smoke produces similar damage, and in fact the most frequent cause of centriacinar emphysema is cigarette smoking. Centriacinar emphysema predominantly involves the upper and posterior portions of the lungs and upper parts of the individual lobes. In severe emphysema, emphysematous spaces may coalesce and form bullae which may reach several centimeters in diameters. By definition bulla is at least 1 cm in diameter. Bullae are usually located in the lung apices and subpleu-

*Centriacinar emphysema and interstitial fibrosis caused by birefringent silica/silicate particles from coal mine dust. This is the same area as in* **Figure 4***, but with original magnification × 400 and photographed under polarized light to highlight birefringent silica/silicate particles; small white dots in the interstitium and silvery* 

rally but can occur anywhere in the emphysematous lungs.

#### **Figure 4.**

*Update in Respiratory Diseases*

and measures about 1.5–3 cm.

diameter of 7.5 mm. There are about three generations of respiratory bronchioles inside the acinus and approximately 25,000 acini in normal adult male lungs with a volume of 5.25 liters [2]. Cluster of three to five terminal bronchioles, that is, acini, form pulmonary lobule. The pulmonary lobule is an anatomic unit, polygonal in shape, and bound by complete or incomplete connective tissue interlobular septa

Gas exchange starts in respiratory bronchioles and mainly occurs in alveoli. The alveolar wall (also called alveolar septum) is very thin in order to permit efficient gas exchange (**Figure 3**). It consists only of one layer of epithelial cells called pneumocytes. Pneumocytes type 1 are very thin, flat, large epithelial cells that cover 90% of the alveolar surface and are not capable of mitosis. Pneumocytes type 2 are cuboidal cell with large basal nucleus and prominent nucleolus.

Pneumocytes type 2 secrete surfactant, are able to divide and participate in repair, and may become hyperplastic in response to alveolar damage. Pneumocytes type 2 are also precursors of pneumocytes type 1. Pneumocytes lie on the basal membrane that is fused with the basal membrane of the capillary endothelial cell. Thus the alveolar wall (septum) consists only of capillary sandwiched between the two layers of pneumocytes from two adjacent alveoli (**Figure 3**). An occasional myofibroblast may be present in the alveolar wall as well as rare scattered small lymphocytes, rare mesenchymal cells, and rare macrophages. Hematoxylin and eosin-stained sections of the normal lung on high magnification show delicate alveolar walls (septa) containing inconspicuous capillaries, occasional cuboidal cells of pneumocytes type 2, and nuclei of pneumocytes type 1, endothelial cell nuclei, and nuclei of rare scattered lymphocytes, mesenchymal cells, and macrophages. The cytoplasm of pneumocytes type 1 is too thin to be visible without special immunoperoxidase stains. Alveolar macrophages egress from capillaries, are increased in number in chronic inflammatory settings, and are involved in phagocytosis of foreign material as well in the inflammatory and immune

The interstitium provides the connective tissue framework of the lungs and is composed of collagen fibers, elastic fibers, mesenchymal cells, and few inflammatory cells. In normal lungs the interstitium is generally inconspicuous and can be recognized only along bronchovascular bundles, around veins, and where it forms interlobular septa. In the children up to 4 years of age, the interstitium is more apparent and presents as thickening of the alveolar walls [3]. The term "small airways" includes airways with diameter of 2 mm and smaller and thus includes small bronchi, terminal bronchioles, and respiratory

Emphysema is permanent enlargement of airspaces distal to the terminal bronchiole (acinus) due to the destruction of the walls of the alveoli, alveolar ducts, and

According to the location of the hyperinflated alveoli inside the acinus, there are four types of emphysema: centriacinar (centrilobular, proximal), panacinar (panlobular), distal acinar (paraseptal), and irregular (associated with scar). Each of the emphysema type has characteristic microscopic morphology and characteristic

The most frequent is centriacinar emphysema which comprises more than 95% of all emphysemas. **Centriacinar emphysema** involves proximal respiratory bronchiolus and adjacent alveoli, which is in the center of the acinus, hence the name

the respiratory bronchioles. Grossly, the lung is hyperinflated and spongy.

**2.2 Morphologic and histologic features of emphysema**

**38**

etiology.

centriacinar emphysema (**Figure 4**).

responses.

bronchioles.

*Centriacinar emphysema caused by coal mine dust. Some alveoli are normal, some emphysematous. Hematoxylin and eosin stain, original magnification 20×.*

Inhaled cigarette smoke or mineral dust, most frequently coal mine dust, reach respiratory bronchioles. There are no cilia in the respiratory bronchioles; cigarette smoke particles and coal dust particles (silica particles in the coal dust are the most toxic ones) stick there and initiate processes of inflammation and destruction. The first damaged structure is thus respiratory bronchiolus with its dilatation or disappearance. In the beginning, alveolar ducts and alveoli are spared. Soon their destruction and coalescence into the larger air space follows. In the acinus, which contains several (about 14) respiratory bronchioles, some bronchioles and alveoli are damaged, enlarged, and emphysematous, and some are not damaged and are normal in size. Thus characteristic microscopic feature with low power magnification of centroacinar emphysema is that some alveoli are normal and some emphysematous (**Figures 4** and **5**).

Cigarette smoke produces similar damage, and in fact the most frequent cause of centriacinar emphysema is cigarette smoking. Centriacinar emphysema predominantly involves the upper and posterior portions of the lungs and upper parts of the individual lobes. In severe emphysema, emphysematous spaces may coalesce and form bullae which may reach several centimeters in diameters. By definition bulla is at least 1 cm in diameter. Bullae are usually located in the lung apices and subpleurally but can occur anywhere in the emphysematous lungs.

#### **Figure 5.**

*Centriacinar emphysema and interstitial fibrosis caused by birefringent silica/silicate particles from coal mine dust. This is the same area as in* **Figure 4***, but with original magnification × 400 and photographed under polarized light to highlight birefringent silica/silicate particles; small white dots in the interstitium and silvery collagen fibers of interstitial (septal alveolar) fibrosis.*

**Panacinar emphysema (panlobular emphysema)** comprises 1% of emphysemas. It involves the entire acinus, that is, all alveoli in the acinus are about equally dilated, and all acini in the lobule are involved by panacinar (panlobular) emphysema (**Figure 6**). In centriacinar emphysema, some alveoli are enlarged and some are normal.

Panacinar emphysema is associated with alpha-1-antitrypsin deficiency, an autosomal codominant genetic disorder. Since defect is present in the gene (chromosome 14, segment q32.1), every cell, in which this gene is active and its product anti-protease alpha-1 antitrypsin enzyme pertinent, is affected. Thus all respiratory bronchioles, alveolar ducts, and alveoli are affected and about equally damaged and equally hyperinflated. The lungs are diffusely affected by panacinar emphysema, and histologically there is diffuse enlargement of the alveoli affecting the entire acinus. Normal level of alpha-1 antitrypsin in the serum is 20–48 μM/L.P atients with emphysema have concentration of serum alpha-1 antitrypsin 2.5–7 μM/L, and they are homozygous for PI\*ZZ allele (PI\* denotes protein inhibitor gene). There are more than 90 different alleles of PI\* gene, and some variants cause a change in conformation of the alpha-1-antitrypsin molecule leading to polymerization and retention of misshaped protein in hepatocytes (major site of synthesis of alpha-1 antitrypsin) that might lead in children as well in adults to cirrhosis of the liver. If there is absence of protein inhibitor gene, serum level of alpha-1 antitrypsin is zero. Panacinar emphysema might also occur in intravenous drug abusers and then is accompanied with talc granulomas and interstitial fibrosis [3, 4]. Birefringent particles of talk could be seen under polarized light in the granulomas and in the fibrotic interstitium (**Figure 7**).

**Distal acinar emphysema (paraseptal emphysema)** involves distal part of the acinus including alveolar ducts and alveoli. It is rare. Distal acinar emphysema is most often present in the upper lobes beneath the pleura and along septa between lobules and also is called paraseptal, subpleural, or localized emphysema. The pathogenesis of distal acinar emphysema is unknown. Distal acinar emphysema produces apical bullae which may cause spontaneous pneumothorax in young adults.

**Irregular emphysema** is airspace enlargement due to lung destruction associated with scarring, also termed scar emphysema, paracicatrical emphysema, and perifocal emphysema. Foci of irregular emphysema are asymptomatic and clinically insignificant. The National Heart, Lung, and Blood Institute does not regard irregular emphysema as a form of emphysema but as "airspace enlargement with fibrosis" [5].

#### **Figure 6.**

*Panacinar emphysema (left) and normal lung (right). In panacinar emphysema, all alveoli are enlarged. Figure 6, is reproduced with permission from the American Registry of Pathology from the Atlas of Nontumor Pathology Series; Non-Neoplastic Disorders of the Lower Respiratory Tract by William D. Travis et al published by the American Registry of Pathology and the Armed Forces Institute of Pathology Washington DC, USA, Copyright© 2002.*

**41**

*Emphysema*

**Figure 7.**

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

*Pathology Washington DC, USA, Copyright© 2002.*

The pathogenesis of centriacinar and panacinar emphysema is conceptually similar and based on proteinase-antiproteinase imbalance, that is, inequity between enzymes that degrade the extracellular matrix and proteins that oppose this proteolytic activity [6]. The first clue appeared in 1963 when Laurell and Eriksson identified patients with alpha-1 antitrypsin (more appropriate name is alpha-1 antiproteinase) deficiency on serum electrophoresis who had severe emphysema of early onset and in 1964 when Gross and coworkers demonstrated that proteolytic enzyme papain can produce emphysema in rats [7, 8]. Alpha-1 antitrypsin is a proteinase inhibitor that inhibits proteolytic enzymes, primarily neutrophil elastase. Elastase is an enzyme that destroys elastin fibers, and if it is not adequately inhibited by alpha-1 antitrypsin, destruction of acinar tissue follows leading to emphysema. Imbalance between other proteolytic enzymes (metalloproteinases including interstitial collagenase-1, interstitial collagenase-3, metalloelastase, matrilysin, gelatinase A and gelatinase B, cathepsins) and their inhibitors (tissue inhibitors of matrix metalloproteinases, elafin, epithelium-derived secretory leukoprotease inhibitor) also contributes to emphysema and chronic obstructive pulmonary disease [3, 6]. Cigarette smoking is the most frequent cause of emphysema and accounts to 80–90% of chronic obstructive pulmonary disease cases in the USA [9]. Cigarette smoke and coal mine dust cause emphysema by a similar pathophysiologic pathway. Inhaled cigarette smoke as well as coal mining dust particles travel by airflow to respiratory bronchioles and alveoli where they interfere with epithelial cells, alveolar macrophages, and neutrophils. Cigarette smoke contains per puff an estimated 1015–1017 oxidants/free radicals and about 4700 different chemical compounds, including reactive aldehydes and quinones [10, 11]. Toxic oxidant compounds in cigarette smoke induce DNA damage and peroxidation of lipids, harm proteins, fold proteins, and cause them to aggregate in the cytoplasm of the respiratory cells and alveolar cells [12]. Alveolar epithelial cells and macrophages damaged by cigarette smoke release cytokines which invite inside alveoli

*Panacinar emphysema caused by drug abuse. Mild interstitial fibrosis is present as well as birefringent deposits of talc in the interstitium. Figure 7 is reproduced with permission from the American Registry of Pathology from the Atlas of Nontumor Pathology Series; Non-Neoplastic Disorders of the Lower Respiratory Tract by William D. Travis et al published by the American Registry of Pathology and the Armed Forces Institute of* 

#### **Figure 7.**

*Update in Respiratory Diseases*

**Panacinar emphysema (panlobular emphysema)** comprises 1% of emphysemas. It involves the entire acinus, that is, all alveoli in the acinus are about equally dilated, and all acini in the lobule are involved by panacinar (panlobular) emphysema (**Figure 6**). In

Panacinar emphysema is associated with alpha-1-antitrypsin deficiency, an autosomal codominant genetic disorder. Since defect is present in the gene (chromosome 14, segment q32.1), every cell, in which this gene is active and its product anti-protease alpha-1 antitrypsin enzyme pertinent, is affected. Thus all respiratory bronchioles, alveolar ducts, and alveoli are affected and about equally damaged and equally hyperinflated. The lungs are diffusely affected by panacinar emphysema, and histologically there is diffuse enlargement of the alveoli affecting the entire acinus. Normal level of alpha-1 antitrypsin in the serum is 20–48 μM/L.P atients with emphysema have concentration of serum alpha-1 antitrypsin 2.5–7 μM/L, and they are homozygous for PI\*ZZ allele (PI\* denotes protein inhibitor gene). There are more than 90 different alleles of PI\* gene, and some variants cause a change in conformation of the alpha-1-antitrypsin molecule leading to polymerization and retention of misshaped protein in hepatocytes (major site of synthesis of alpha-1 antitrypsin) that might lead in children as well in adults to cirrhosis of the liver. If there is absence of protein inhibitor gene, serum level of alpha-1 antitrypsin is zero. Panacinar emphysema might also occur in intravenous drug abusers and then is accompanied with talc granulomas and interstitial fibrosis [3, 4]. Birefringent particles of talk could be seen under polarized light in the granulomas and in the fibrotic interstitium (**Figure 7**). **Distal acinar emphysema (paraseptal emphysema)** involves distal part of the acinus including alveolar ducts and alveoli. It is rare. Distal acinar emphysema is most often present in the upper lobes beneath the pleura and along septa between lobules and also is called paraseptal, subpleural, or localized emphysema. The pathogenesis of distal acinar emphysema is unknown. Distal acinar emphysema produces apical bullae which may cause spontaneous pneumothorax in young adults. **Irregular emphysema** is airspace enlargement due to lung destruction associated with scarring, also termed scar emphysema, paracicatrical emphysema, and perifocal emphysema. Foci of irregular emphysema are asymptomatic and clinically insignificant. The National Heart, Lung, and Blood Institute does not regard irregular emphysema as a form of emphysema but as "airspace enlargement with fibrosis" [5].

*Panacinar emphysema (left) and normal lung (right). In panacinar emphysema, all alveoli are enlarged. Figure 6, is reproduced with permission from the American Registry of Pathology from the Atlas of Nontumor Pathology Series; Non-Neoplastic Disorders of the Lower Respiratory Tract by William D. Travis et al published by the American Registry of Pathology and the Armed Forces Institute of Pathology Washington DC,* 

centriacinar emphysema, some alveoli are enlarged and some are normal.

**40**

**Figure 6.**

*USA, Copyright© 2002.*

*Panacinar emphysema caused by drug abuse. Mild interstitial fibrosis is present as well as birefringent deposits of talc in the interstitium. Figure 7 is reproduced with permission from the American Registry of Pathology from the Atlas of Nontumor Pathology Series; Non-Neoplastic Disorders of the Lower Respiratory Tract by William D. Travis et al published by the American Registry of Pathology and the Armed Forces Institute of Pathology Washington DC, USA, Copyright© 2002.*

The pathogenesis of centriacinar and panacinar emphysema is conceptually similar and based on proteinase-antiproteinase imbalance, that is, inequity between enzymes that degrade the extracellular matrix and proteins that oppose this proteolytic activity [6]. The first clue appeared in 1963 when Laurell and Eriksson identified patients with alpha-1 antitrypsin (more appropriate name is alpha-1 antiproteinase) deficiency on serum electrophoresis who had severe emphysema of early onset and in 1964 when Gross and coworkers demonstrated that proteolytic enzyme papain can produce emphysema in rats [7, 8]. Alpha-1 antitrypsin is a proteinase inhibitor that inhibits proteolytic enzymes, primarily neutrophil elastase. Elastase is an enzyme that destroys elastin fibers, and if it is not adequately inhibited by alpha-1 antitrypsin, destruction of acinar tissue follows leading to emphysema. Imbalance between other proteolytic enzymes (metalloproteinases including interstitial collagenase-1, interstitial collagenase-3, metalloelastase, matrilysin, gelatinase A and gelatinase B, cathepsins) and their inhibitors (tissue inhibitors of matrix metalloproteinases, elafin, epithelium-derived secretory leukoprotease inhibitor) also contributes to emphysema and chronic obstructive pulmonary disease [3, 6].

Cigarette smoking is the most frequent cause of emphysema and accounts to 80–90% of chronic obstructive pulmonary disease cases in the USA [9]. Cigarette smoke and coal mine dust cause emphysema by a similar pathophysiologic pathway. Inhaled cigarette smoke as well as coal mining dust particles travel by airflow to respiratory bronchioles and alveoli where they interfere with epithelial cells, alveolar macrophages, and neutrophils. Cigarette smoke contains per puff an estimated 1015–1017 oxidants/free radicals and about 4700 different chemical compounds, including reactive aldehydes and quinones [10, 11]. Toxic oxidant compounds in cigarette smoke induce DNA damage and peroxidation of lipids, harm proteins, fold proteins, and cause them to aggregate in the cytoplasm of the respiratory cells and alveolar cells [12]. Alveolar epithelial cells and macrophages damaged by cigarette smoke release cytokines which invite inside alveoli

#### *Update in Respiratory Diseases*

inflammatory cells mainly macrophages but also T cells (T8 more than T4) and small number of neutrophils. Characteristic histologic findings in cigarette smokers are tobacco-associated respiratory bronchiolitis with the presence of macrophages containing smoker granules (yellow-brown) inside alveoli (**Figure 8**). Macrophages and neutrophils activated by cigarette smoke or silica (quartz) [13] particles in coal mine dust release abovementioned proteolytic enzymes that destroy collagen and elastic alveolar tissue causing connective tissue breakdown and alveolar tissue destruction, that is, emphysema [14]. Oxidative radicals in the cigarette smoke as well as quartz-generated hydrogen peroxide not only damage intracellular proteins but also inactivate alpha-1 antitrypsin by oxidizing the SH group of methionine to methionine sulfoxide [14]. Other proteins, for example, proteasome with caspaselike activity, are also impaired by this oxidation. The final effect of cigarette smoke and inhalation of coal mine dust is unopposed (or insufficiently inhibited) action of proteolytic enzymes that destroy lung parenchyma and cause emphysema.

Macrophages also produce transforming growth factor-beta, platelet-derived growth factor, and tumor necrosis-alpha, which all stimulate fibroblast growth, collagen production and repair with associated fibrosis [15]. Repair may not be perfect and interstitial fibrosis may occur. Bronchioles and small bronchi can be involved by fibrosis and contribute to the chronic obstructive pulmonary disease. Tobaccocaused respiratory bronchiolitis-associated interstitial lung disease with fibrosis (**Figure 9**) is now a plausible and established term [16, 17].

#### **Figure 8.**

*Tobacco-associated respiratory bronchiolitis. Macrophages with smoker granules inside alveoli. Hematoxylin and eosin stain, original magnification 400×.*

#### **Figure 9.**

*Tobacco-associated respiratory bronchiolitis with interstitial fibrosis. Hematoxylin and eosin stain, original magnification 200×. Right, same picture under polarized light to demonstrate collagen (silvery shine) fibers in thickened fibrotic alveolar septa.*

**43**

**Figure 11.**

*Emphysema*

**Figure 10.**

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

alveolar macrophages (**Figure 10**) [18].

*silica particles, and small bright dots are silicate particles.*

emphysema syndrome (**Figure 11**) may occur [18, 19].

It is obvious that tobacco-associated emphysema and tobacco-associated interstitial fibrosis are related and that the first step in their genesis is accumulation of macrophages with smoker granules in the alveoli. The similar process can be elicited by silica and silicates from coal mine dust. The first sign of exposure to coal mine dust is accumulation of silica/silicate particles and anthracotic pigment in the

*Initial event in development of emphysema and interstitial fibrosis in coal miners is appearance of macrophages laden with silica and silicate particles and anthracotic pigment inside alveoli. Hematoxylin and eosin stain, original magnification 400×. Right side, same picture under polarized light to demonstrate birefringent silica and silicate particles in the cytoplasm of macrophages. Very small and faint white dots are* 

In coal miners with complicated coal worker's pneumoconiosis, the role of smoking in causing fibrosis is insignificant in comparison with that of silica/silicate particles from coal mine dust [18]. Since smoking and coal mine dust simultaneously may cause pulmonary fibrosis and emphysema by destruction of lung tissue and healing by fibrosis, it is plausible that in some patients emphysema is dominant, in others interstitial fibrosis, and in some others combined pulmonary fibrosis and

Alpha-1 antitrypsin deficiency is not the only one known genetic cause of emphysema. Telomere length is also associated with emphysema [20]. Both tips (ends) of the chromosomes are capped (protected) by telomeres composed of tandemly repeated DNA sequences. Telomeres are highly conserved and practically identical from protozoa to vertebrates. In humans, the TTAGGG repeat region is 10–15 kilobytes long. With each mitosis terminal nucleotides at the tail of telomeres are lost, and telomeres become shorter with each cell division. When telomere becomes critically short, the cell cannot

*Tobacco caused emphysema and tobacco caused respiratory bronchiolitis-associated interstitial lung disease with fibrosis, called combined pulmonary fibrosis and emphysema syndrome. Courtesy of Dr. Nadia N. Naumova.*

#### **Figure 10.**

*Update in Respiratory Diseases*

inflammatory cells mainly macrophages but also T cells (T8 more than T4) and small number of neutrophils. Characteristic histologic findings in cigarette smokers are tobacco-associated respiratory bronchiolitis with the presence of macrophages containing smoker granules (yellow-brown) inside alveoli (**Figure 8**). Macrophages and neutrophils activated by cigarette smoke or silica (quartz) [13] particles in coal mine dust release abovementioned proteolytic enzymes that destroy collagen and elastic alveolar tissue causing connective tissue breakdown and alveolar tissue destruction, that is, emphysema [14]. Oxidative radicals in the cigarette smoke as well as quartz-generated hydrogen peroxide not only damage intracellular proteins but also inactivate alpha-1 antitrypsin by oxidizing the SH group of methionine to methionine sulfoxide [14]. Other proteins, for example, proteasome with caspaselike activity, are also impaired by this oxidation. The final effect of cigarette smoke and inhalation of coal mine dust is unopposed (or insufficiently inhibited) action of

proteolytic enzymes that destroy lung parenchyma and cause emphysema.

(**Figure 9**) is now a plausible and established term [16, 17].

Macrophages also produce transforming growth factor-beta, platelet-derived growth factor, and tumor necrosis-alpha, which all stimulate fibroblast growth, collagen production and repair with associated fibrosis [15]. Repair may not be perfect and interstitial fibrosis may occur. Bronchioles and small bronchi can be involved by fibrosis and contribute to the chronic obstructive pulmonary disease. Tobaccocaused respiratory bronchiolitis-associated interstitial lung disease with fibrosis

*Tobacco-associated respiratory bronchiolitis. Macrophages with smoker granules inside alveoli. Hematoxylin* 

*Tobacco-associated respiratory bronchiolitis with interstitial fibrosis. Hematoxylin and eosin stain, original magnification 200×. Right, same picture under polarized light to demonstrate collagen (silvery shine) fibers in* 

**42**

**Figure 9.**

*thickened fibrotic alveolar septa.*

**Figure 8.**

*and eosin stain, original magnification 400×.*

*Initial event in development of emphysema and interstitial fibrosis in coal miners is appearance of macrophages laden with silica and silicate particles and anthracotic pigment inside alveoli. Hematoxylin and eosin stain, original magnification 400×. Right side, same picture under polarized light to demonstrate birefringent silica and silicate particles in the cytoplasm of macrophages. Very small and faint white dots are silica particles, and small bright dots are silicate particles.*

It is obvious that tobacco-associated emphysema and tobacco-associated interstitial fibrosis are related and that the first step in their genesis is accumulation of macrophages with smoker granules in the alveoli. The similar process can be elicited by silica and silicates from coal mine dust. The first sign of exposure to coal mine dust is accumulation of silica/silicate particles and anthracotic pigment in the alveolar macrophages (**Figure 10**) [18].

In coal miners with complicated coal worker's pneumoconiosis, the role of smoking in causing fibrosis is insignificant in comparison with that of silica/silicate particles from coal mine dust [18]. Since smoking and coal mine dust simultaneously may cause pulmonary fibrosis and emphysema by destruction of lung tissue and healing by fibrosis, it is plausible that in some patients emphysema is dominant, in others interstitial fibrosis, and in some others combined pulmonary fibrosis and emphysema syndrome (**Figure 11**) may occur [18, 19].

Alpha-1 antitrypsin deficiency is not the only one known genetic cause of emphysema. Telomere length is also associated with emphysema [20]. Both tips (ends) of the chromosomes are capped (protected) by telomeres composed of tandemly repeated DNA sequences. Telomeres are highly conserved and practically identical from protozoa to vertebrates. In humans, the TTAGGG repeat region is 10–15 kilobytes long. With each mitosis terminal nucleotides at the tail of telomeres are lost, and telomeres become shorter with each cell division. When telomere becomes critically short, the cell cannot

#### **Figure 11.**

*Tobacco caused emphysema and tobacco caused respiratory bronchiolitis-associated interstitial lung disease with fibrosis, called combined pulmonary fibrosis and emphysema syndrome. Courtesy of Dr. Nadia N. Naumova.*

divide anymore and thus becomes an old cell that will finally end up in apoptosis. Telomerase is an enzyme that synthesizes telomeres. Mutations in telomerase gene and telomere genes cause short telomere length for cell age and disease spectrum called short telomere syndrome/accelerated aging syndrome. The main presentation (90%) of short telomere syndromes are idiopathic pulmonary (interstitial) fibrosis and emphysema. They may be associated with other features of premature aging including early graying, osteoporosis, liver disease, predisposition to bone marrow failure, infertility, as well as myelodysplastic syndrome and acute myeloid leukemia [21]. Reduced telomere length may be identified in 25% of patients with sporadic idiopathic pulmonary fibrosis and half of those cases with family aggregation [22]. Telomerase deficiency and telomere shortening are responsible for only 1% of all emphysemas but are conceptually important as a link between interstitial fibrosis, emphysema, combined emphysema and interstitial fibrosis, and effect of environment on phenotypic presentation of genetic defect [21]. Pathogenic mechanism is premature senescence of alveolar epithelial stem cells, their apoptosis, disappearance of alveoli (emphysema), and abnormal repair with excessive interstitial fibrosis. The same genetic change, germline deletion in the Box H domain of the RNA telomerase, can cause in the father idiopathic pulmonary fibrosis, in one daughter emphysema, and in the other daughter combined pulmonary fibrosis and emphysema syndrome [20]. Interaction between the gene and environment determines lung disease. Never-smokers develop pulmonary interstitial fibrosis, while smokers develop an early onset emphysema alone or combined emphysema and pulmonary interstitial fibrosis [20, 21]. Cigarette smoke causes additive DNA damage to telomere function, and genetic defect in this setting expresses as emphysema [20].

In short, the main causes of emphysema and interstitial fibrosis are cigarette smoking and in coal miners silica and silicate particles from coal dust. Hereditary emphysemas caused by alpha-1 antitrypsin deficiency and short telomere length are epidemiologically insignificant but can help to elucidate pathogenesis of emphysema and interstitial fibrosis. Not all smokers develop emphysema and chronic obstructive pulmonary disease. Only 10–20% of the smokers develop chronic obstructive pulmonary disease pointing at an additional risk factor such as genetic susceptibility reflected in polymorphisms in genes coding for various antiproteases, a disintegrin, and metalloproteinase 33 or antioxidant superoxide dismutase and proinflammatory mediators including tumor necrosis factor-alpha [10] and possibly genes associated with telomeres. Combined pulmonary fibrosis and emphysema are also in the vast majority of cases caused by cigarette smoking or in coal miners by coal dust, and the above mentioned genetic factors might contribute to a now unknown degree of susceptibility.

Patients with emphysema only are extremely rare, and in practice emphysema is component of the chronic obstructive pulmonary disease which affects about 24 million people in the USA. Chronic bronchitis is chronic mucous hypersecretion syndrome and is clinically defined as productive cough for at least 3 months in 2 successive years. Its pathohistological features (**Figure 12**) include enlargement of the mucus-secreting glands in the bronchial wall, goblet cell metaplasia of the respiratory epithelium, infiltration of the bronchial mucosa with lymphocytes, squamous metaplasia and dysplasia in the bronchial epithelium, increased bronchial smooth muscle, as well as mucous plugging, inflammation, and fibrosis of the bronchioles.

Chronic bronchitis becomes chronic obstructive bronchitis when airflow obstruction occurs. It can be detected by spirometry or expiratory wheezing can be heard by auscultation. Bronchial airways are being compressed during expiration, and expiration is in chronic obstructive bronchitis difficult and prolonged. Auscultation reveals diminished breath sounds, prolonged expiratory phase, and expiratory wheezing. The main airflow obstruction occurs in small airways, with diameter less than 2 mm. Obstruction is caused by mucosal thickening, due to lymphocytic infiltration, fibrosis, edema, mucous plugging, and smooth muscle hypertrophy. **Figure 13** demonstrates

**45**

*Emphysema*

**Figure 12.**

**Figure 13.**

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

thickening of the wall of the terminal bronchiolus by fibrous tissue and smooth muscle

*The wall of the terminal bronchiolus is thickened by fibrosis and smooth muscle hypertrophy and this is one of the essential pathologic bases for obstructive pulmonary disease. Birefringent silica and silicate particles are* 

*Chronic bronchitis presenting with mucus in the lumen of the bronchus, partial goblet cell metaplasia of the respiratory epithelium, predominance of the mucinous cells in the bronchial exocrine gland, infiltration the bronchial wall by small lymphocytes and plasma cells, hypertrophy of the muscle layer, and peribronchial fibrosis.*

Clara cells that secrete surfactant are replaced by goblet cells, and decrease of surfactant increases surface tension at the air-tissue interface, and small bronchi and bronchiole are prone to collapse. Emphysema also contributes to airflow obstruction. Destruction and disappearance of respiratory bronchiole and alveolar ducts decrease total airway diameter. Destruction of acinar tissue with disappearance of elastic fibers decreases lung recoil and decreases expiratory air force. The net effect of chronic obstructive pulmonary disease is difficulty in breathing, prolonged expiration with expiratory wheezing, air trapping in the lungs with hyperinflation

hypertrophy caused by birefringent silica/silicate particles from coal mine dust.

*etiological factor. Hematoxylin and eosin stain, original magnification 200×, polarized light.*

of lungs, increased residual volume, decreased vital capacity, and dyspnea.

Three cardinal features of chronic obstructive pulmonary disease are cough, sputum production, and exertional dyspnea. Dyspnea during physical activity may start insidiously, and patients complain of difficult breathing, gasping and air hunger, heaviness in chest in the beginning only during rather heavy physical work and later during light daily physical activity. Patients with chronic obstructive pulmonary disease poorly tolerate physical activity with arms but tolerate better physical work like pushing shopping cart when arms are fixed and enable the use of accessory respiratory muscles [1]. Acute exacerbations of chronic obstructive pulmonary

#### **Figure 12.**

*Update in Respiratory Diseases*

divide anymore and thus becomes an old cell that will finally end up in apoptosis. Telomerase is an enzyme that synthesizes telomeres. Mutations in telomerase gene and telomere genes cause short telomere length for cell age and disease spectrum called short telomere syndrome/accelerated aging syndrome. The main presentation (90%) of short telomere syndromes are idiopathic pulmonary (interstitial) fibrosis and emphysema. They may be associated with other features of premature aging including early graying, osteoporosis, liver disease, predisposition to bone marrow failure, infertility, as well as myelodysplastic syndrome and acute myeloid leukemia [21]. Reduced telomere length may be identified in 25% of patients with sporadic idiopathic pulmonary fibrosis and half of those cases with family aggregation [22]. Telomerase deficiency and telomere shortening are responsible for only 1% of all emphysemas but are conceptually important as a link between interstitial fibrosis, emphysema, combined emphysema and interstitial fibrosis, and effect of environment on phenotypic presentation of genetic defect [21]. Pathogenic mechanism is premature senescence of alveolar epithelial stem cells, their apoptosis, disappearance of alveoli (emphysema), and abnormal repair with excessive interstitial fibrosis. The same genetic change, germline deletion in the Box H domain of the RNA telomerase, can cause in the father idiopathic pulmonary fibrosis, in one daughter emphysema, and in the other daughter combined pulmonary fibrosis and emphysema syndrome [20]. Interaction between the gene and environment determines lung disease. Never-smokers develop pulmonary interstitial fibrosis, while smokers develop an early onset emphysema alone or combined emphysema and pulmonary interstitial fibrosis [20, 21]. Cigarette smoke causes additive DNA damage to telomere function, and genetic defect in this setting expresses as emphysema [20]. In short, the main causes of emphysema and interstitial fibrosis are cigarette smoking and in coal miners silica and silicate particles from coal dust. Hereditary emphysemas caused by alpha-1 antitrypsin deficiency and short telomere length are epidemiologically insignificant but can help to elucidate pathogenesis of emphysema and interstitial fibrosis. Not all smokers develop emphysema and chronic obstructive pulmonary disease. Only 10–20% of the smokers develop chronic obstructive pulmonary disease pointing at an additional risk factor such as genetic susceptibility reflected in polymorphisms in genes coding for various antiproteases, a disintegrin, and metalloproteinase 33 or antioxidant superoxide dismutase and proinflammatory mediators including tumor necrosis factor-alpha [10] and possibly genes associated with telomeres. Combined pulmonary fibrosis and emphysema are also in the vast majority of cases caused by cigarette smoking or in coal miners by coal dust, and the above mentioned genetic factors might contribute to a now unknown degree of susceptibility. Patients with emphysema only are extremely rare, and in practice emphysema is component of the chronic obstructive pulmonary disease which affects about 24 million people in the USA. Chronic bronchitis is chronic mucous hypersecretion syndrome and is clinically defined as productive cough for at least 3 months in 2 successive years. Its pathohistological features (**Figure 12**) include enlargement of the mucus-secreting glands in the bronchial wall, goblet cell metaplasia of the respiratory epithelium, infiltration of the bronchial mucosa with lymphocytes, squamous metaplasia and dysplasia in the bronchial epithelium, increased bronchial smooth muscle, as well as mucous plugging, inflammation, and fibrosis of the bronchioles. Chronic bronchitis becomes chronic obstructive bronchitis when airflow obstruction occurs. It can be detected by spirometry or expiratory wheezing can be heard by auscultation. Bronchial airways are being compressed during expiration, and expiration is in chronic obstructive bronchitis difficult and prolonged. Auscultation reveals diminished breath sounds, prolonged expiratory phase, and expiratory wheezing. The main airflow obstruction occurs in small airways, with diameter less than 2 mm. Obstruction is caused by mucosal thickening, due to lymphocytic infiltration, fibrosis, edema, mucous plugging, and smooth muscle hypertrophy. **Figure 13** demonstrates

**44**

*Chronic bronchitis presenting with mucus in the lumen of the bronchus, partial goblet cell metaplasia of the respiratory epithelium, predominance of the mucinous cells in the bronchial exocrine gland, infiltration the bronchial wall by small lymphocytes and plasma cells, hypertrophy of the muscle layer, and peribronchial fibrosis.*

#### **Figure 13.**

*The wall of the terminal bronchiolus is thickened by fibrosis and smooth muscle hypertrophy and this is one of the essential pathologic bases for obstructive pulmonary disease. Birefringent silica and silicate particles are etiological factor. Hematoxylin and eosin stain, original magnification 200×, polarized light.*

thickening of the wall of the terminal bronchiolus by fibrous tissue and smooth muscle hypertrophy caused by birefringent silica/silicate particles from coal mine dust.

Clara cells that secrete surfactant are replaced by goblet cells, and decrease of surfactant increases surface tension at the air-tissue interface, and small bronchi and bronchiole are prone to collapse. Emphysema also contributes to airflow obstruction. Destruction and disappearance of respiratory bronchiole and alveolar ducts decrease total airway diameter. Destruction of acinar tissue with disappearance of elastic fibers decreases lung recoil and decreases expiratory air force. The net effect of chronic obstructive pulmonary disease is difficulty in breathing, prolonged expiration with expiratory wheezing, air trapping in the lungs with hyperinflation of lungs, increased residual volume, decreased vital capacity, and dyspnea.

Three cardinal features of chronic obstructive pulmonary disease are cough, sputum production, and exertional dyspnea. Dyspnea during physical activity may start insidiously, and patients complain of difficult breathing, gasping and air hunger, heaviness in chest in the beginning only during rather heavy physical work and later during light daily physical activity. Patients with chronic obstructive pulmonary disease poorly tolerate physical activity with arms but tolerate better physical work like pushing shopping cart when arms are fixed and enable the use of accessory respiratory muscles [1]. Acute exacerbations of chronic obstructive pulmonary

disease are prominent feature of its natural history and are characterized by cough, increase in amount and character (color) of sputum, and dyspnea and may or may not be accompanied with fever, myalgia, and sore throat. The health-related quality of life of patients with chronic obstructive pulmonary disease better correlates (inverse correlation) with frequency of acute exacerbations than with the degree of airflow obstruction (Reilly-Harrison). Patients with advanced emphysema due to hyperinflation of lungs have barrel chest with poor diaphragmatic excursion as assessed by percussion and dramatic decrease in breath sounds and are sitting in the characteristic tripod position with stretched fixed arms to enable the use of accessory respiratory muscles including sternocleidomastoid, scalene, and intercostal ones [1]. Patients with predominant emphysema are called "pink puffers" because they breathe through pursed lips with the help of accessory respiratory muscles. When small airway obstruction ensues, patients become hypoxic and cyanotic in the lips and nail beds, and when fluid retains due to right heart decompensation, they become "blue bloaters." However the majority of chronic obstructive pulmonary disease patients have some signs of both, "pink puffers" and "blue bloaters." Advanced chronic obstructive lung disease is accompanied by systemic wasting due to high energy expenditure for increased work of breathing muscles including accessory breathing muscles and elevated levels of inflammatory cytokines including tumor necrosis factor-alpha. Such patients have a significant weight loss and diffuse loss of subcutaneous fatty tissue. Some patients with advanced chronic obstructive pulmonary disease have paradoxical inward movement of the lower rib cage (Hoover sign) due to diaphragmatic contraction in a setting of permanently hyperinflated lungs [1]. Advanced chronic obstructive pulmonary disease, especially during acute exacerbation, can be accompanied by right heart failure. Signs include right ventricular heave, third heart sound, distended jugular veins, congested liver, ascites, and edema of legs.

### **2.3 Radiologic findings**

Cardinal features of emphysema, hyperinflation of the lungs, and lung tissue destruction can be visualized by radiologic means. On the chest roentgenogram hyperinflation presents with increased lucency, increased retrosternal air space, depression and flattening of the diaphragm. Lung destruction presents in focal lucencies and areas of decreased vascularity. Mild emphysema is usually missed by standard chest X-rays.

High-resolution computerized tomography is superior to the chest X-ray in detecting emphysema. High-resolution computerized tomography can visualize focal areas of decreased attenuation sharply circumscribed without visible walls and with small centrilobular vessel in the areas of emphysema [3]. Several studies showed good correlation between the degree of pathologic findings and high-resolution computerized tomography findings [23]. However, mild focal areas might not be detected, and highresolution computerized tomography cannot be used to rule out emphysema [24].

### **2.4 Tests of pulmonary function**

Spirometry and pulse oximetry are basic simple pulmonary function tests that can be performed in the ambulatory settings. The patient exhales in the spirometry instrument as completely as possible, then forcibly inhales as much as possible, and then forcibly exhales as much as possible. Forced vital capacity is the maximum amount of air forcibly expired after maximum inspiration. Residual volume is amount of air retained in the lungs after maximal and forceful exhalation, and it can be calculated after using gas dilution technique or body-box plethysmography. In the emphysema due to the destruction of respiratory bronchioles, spirometry

**47**

*Emphysema*

procedure.

**2.5 Therapy**

**Conflicts of interest**

None declared.

**Author details**

Tomislav M. Jelic

Charleston, West Virginia, USA

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

mixed lung disorder, both obstructive and restrictive.

immunosuppression brings risk of opportunistic infections.

will demonstrate obstructive pattern. Forced expiratory volume in 1 second will be decreased. Alveolar destruction in emphysema decreases amount of lung parenchyma, and thus forced vital capacity will decrease. Essentially emphysema is a

Transcutaneous pulse oximetry estimates oxygen (O2) saturation of capillary blood using instrument in shape of clip positioned on a finger. Estimation is accurate and correlates to 5% of measured atrial O2 saturation obtained by invasive

Centriacinar emphysema is a progressive disabling disease for which there are no good therapeutic options. Large bullae that compress functional lung tissue can be surgically removed. Patients with severe, predominantly upper lung emphysema, and low baseline exercise capacity may benefit from lung volume reduction by resection, including bronchoscopic lung volume reduction, of non-functioning emphysematous areas. Dyspnea decreases because of reduced hyperinflation and residual volume and because forced expiration volume in the first second is increased [25]. Exercise tolerance and 2-year mortality rate are improved supposedly to decreased residual lung volume, enhanced lung recoil, and improved diaphragmatic function. Long-term effects of the lung volume reduction surgery are unknown. Improvement after lung transplantation is better than after the lung volume reduction surgery. Candidates for lung transplantation are younger than 60 years, with an FEV1 less than 25% predicted or pulmonary artery hypertension. The 5-year survival after transplantation for emphysema is 45–60%. Lifelong

provided the original work is properly cited.

\*Address all correspondence to: tomsilav.jelic@camc.org

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Pathology and Laboratory Medicine, Charleston Area Medical Center,

#### *Emphysema DOI: http://dx.doi.org/10.5772/intechopen.83273*

will demonstrate obstructive pattern. Forced expiratory volume in 1 second will be decreased. Alveolar destruction in emphysema decreases amount of lung parenchyma, and thus forced vital capacity will decrease. Essentially emphysema is a mixed lung disorder, both obstructive and restrictive.

Transcutaneous pulse oximetry estimates oxygen (O2) saturation of capillary blood using instrument in shape of clip positioned on a finger. Estimation is accurate and correlates to 5% of measured atrial O2 saturation obtained by invasive procedure.

## **2.5 Therapy**

*Update in Respiratory Diseases*

**2.3 Radiologic findings**

standard chest X-rays.

**2.4 Tests of pulmonary function**

disease are prominent feature of its natural history and are characterized by cough, increase in amount and character (color) of sputum, and dyspnea and may or may not be accompanied with fever, myalgia, and sore throat. The health-related quality of life of patients with chronic obstructive pulmonary disease better correlates (inverse correlation) with frequency of acute exacerbations than with the degree of airflow obstruction (Reilly-Harrison). Patients with advanced emphysema due to hyperinflation of lungs have barrel chest with poor diaphragmatic excursion as assessed by percussion and dramatic decrease in breath sounds and are sitting in the characteristic tripod position with stretched fixed arms to enable the use of accessory respiratory muscles including sternocleidomastoid, scalene, and intercostal ones [1]. Patients with predominant emphysema are called "pink puffers" because they breathe through pursed lips with the help of accessory respiratory muscles. When small airway obstruction ensues, patients become hypoxic and cyanotic in the lips and nail beds, and when fluid retains due to right heart decompensation, they become "blue bloaters." However the majority of chronic obstructive pulmonary disease patients have some signs of both, "pink puffers" and "blue bloaters." Advanced chronic obstructive lung disease is accompanied by systemic wasting due to high energy expenditure for increased work of breathing muscles including accessory breathing muscles and elevated levels of inflammatory cytokines including tumor necrosis factor-alpha. Such patients have a significant weight loss and diffuse loss of subcutaneous fatty tissue. Some patients with advanced chronic obstructive pulmonary disease have paradoxical inward movement of the lower rib cage (Hoover sign) due to diaphragmatic contraction in a setting of permanently hyperinflated lungs [1]. Advanced chronic obstructive pulmonary disease, especially during acute exacerbation, can be accompanied by right heart failure. Signs include right ventricular heave, third heart sound, distended jugular veins, congested liver, ascites, and edema of legs.

Cardinal features of emphysema, hyperinflation of the lungs, and lung tissue destruction can be visualized by radiologic means. On the chest roentgenogram hyperinflation presents with increased lucency, increased retrosternal air space, depression and flattening of the diaphragm. Lung destruction presents in focal lucencies and areas of decreased vascularity. Mild emphysema is usually missed by

High-resolution computerized tomography is superior to the chest X-ray in detecting emphysema. High-resolution computerized tomography can visualize focal areas of decreased attenuation sharply circumscribed without visible walls and with small centrilobular vessel in the areas of emphysema [3]. Several studies showed good correlation between the degree of pathologic findings and high-resolution computerized tomography findings [23]. However, mild focal areas might not be detected, and highresolution computerized tomography cannot be used to rule out emphysema [24].

Spirometry and pulse oximetry are basic simple pulmonary function tests that can be performed in the ambulatory settings. The patient exhales in the spirometry instrument as completely as possible, then forcibly inhales as much as possible, and then forcibly exhales as much as possible. Forced vital capacity is the maximum amount of air forcibly expired after maximum inspiration. Residual volume is amount of air retained in the lungs after maximal and forceful exhalation, and it can be calculated after using gas dilution technique or body-box plethysmography. In the emphysema due to the destruction of respiratory bronchioles, spirometry

**46**

Centriacinar emphysema is a progressive disabling disease for which there are no good therapeutic options. Large bullae that compress functional lung tissue can be surgically removed. Patients with severe, predominantly upper lung emphysema, and low baseline exercise capacity may benefit from lung volume reduction by resection, including bronchoscopic lung volume reduction, of non-functioning emphysematous areas. Dyspnea decreases because of reduced hyperinflation and residual volume and because forced expiration volume in the first second is increased [25]. Exercise tolerance and 2-year mortality rate are improved supposedly to decreased residual lung volume, enhanced lung recoil, and improved diaphragmatic function. Long-term effects of the lung volume reduction surgery are unknown. Improvement after lung transplantation is better than after the lung volume reduction surgery. Candidates for lung transplantation are younger than 60 years, with an FEV1 less than 25% predicted or pulmonary artery hypertension. The 5-year survival after transplantation for emphysema is 45–60%. Lifelong immunosuppression brings risk of opportunistic infections.

## **Conflicts of interest**

None declared.

## **Author details**

Tomislav M. Jelic Department of Pathology and Laboratory Medicine, Charleston Area Medical Center, Charleston, West Virginia, USA

\*Address all correspondence to: tomsilav.jelic@camc.org

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] Reilly J, Silverman E, Shapiro S. Chronic obstructive pulmonary disease. In: Kasper D, Fauci A, Longo D, Braunwald E, Hauser S, Jameson LJ, editors. Harrison's Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005. pp. 1547-1554

[2] Sorokin SP. The respiratory system. In: Weiss L, editor. Cell and Tissue Biology. 6th ed. Baltimore: Urban & Schwarzenberg; 1988. pp. 753-814

[3] Travis W, Colby T, Koss M, de Christenson R, Muller N, King T Jr. Non-Neoplastic Disorders of the Lower Respiratory Tract. Atlas of Nontumor Pathology. AFIP, ARP. pp. 435-471

[4] Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach DD. Panlobular emphysema in young intravenous Ritalin abusers. The American Review of Respiratory Disease. 1991;**143**:649-646

[5] Snider GL, Kleinerman J, Thurlbeck WM, Bengali ZH. The definition of emphysema. Report of a National Heart , Lung, and Blood Institute, Division of Lung Diseases workshop. The American Review of Respiratory Disease. 1985;**132**:182-185

[6] Pardo A, Selman M. Proteinaseantiproteinase imbalance in the pathogenesis of Emphysema: The role of metalloproteinases in lung damage. Histology and Histopathology. 1999;**14**:227-233

[7] Laurell CB, Eriksson S. The electrophoretical alpha1-globulin pattern of serum alpha1-antitrypsin deficiency. Scandinavian Journal of Clinical and Laboratory Investigation. 1963;**15**:132-140

[8] Gross P, Pfitzer EA, Tolker E, Babyok MA, Kaschak M. Experimental emphysema, its production with papain in normal and silicotic rats. Archives of Environmental Health. 1965;**11**:50-58

[9] Sethi S, Rochesert CL. Smoking and chronic obstructive pulmonary disease. Clinics in Chest Medicine. 2000;**21**:67-86

[10] Hongwei Y, Rahman I. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicology and Applied Pharmacology. 2011;**254**(2):72-85

[11] Church DF, Pryor WA. Freeradical chemistry of cigarette smoke and its toxicological implications. Environmental Health Perspectives. 1985;**64**:111-126

[12] Tran I, Ji C, Ni I, Min T, Tang D, Vij N. Role of cigarette smoke-induced aggresome formation in chronic obstructive pulmonary diseaseemphysema pathogenesis. American Journal of Respiratory Cell and Molecular Biology. 2015;**53**(2):159-173

[13] Cohen RA, Petsonk EL, Rose C, et al. Lung pathology in U.S. coal workers with rapidly progressive pneumoconiosis implicates silica and silicates. American Journal of Respiratory and Critical Care Medicine. 1964;(6):673-680

[14] Churg A, Zay K, Li K. Mechanisms of mineral dust-induced emphysema. Environmental Health Perspectives. 1997;**105**(Suppl *5*):1215-1218

[15] Schns RP, Borm PJ. Mechanisms and mediators in coal dust induced toxicity: a review. The Annals of Occupational Hygiene. 1999;**43**(1):7-33

[16] Vassalllo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Seminars in Respiratory and Critical Care Medicine. 2008;**29**(6):643-650

**49**

*Emphysema*

*DOI: http://dx.doi.org/10.5772/intechopen.83273*

bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal. Modern Pathology. 2006;(11):1474-1479

assessment of emphysema. The American Review of Respiratory Disease. 1989;**139**:980-983

[25] Gulsen A. Bronchoscopic lung volume reduction: A 2018 review and update. Turkish Thoracic Journal.

2018;**19**(3):141-149

[18] Jelic TM, Estalilla OC, Sawyer-Kaplan PR, Plata MJ, Powers JT, Emmett M, et al. Coal mine dust desquamative chronic interstitial pneumonia: A precursor of dust-related diffuse fibrosis and of emphysema. International Journal of Occupational

and Environmental Medicine.

[19] Jankowich MD, Rounds

[20] Alder JK, Guo N, Parry EM, Anderson CJ, Gorgy AI, Walshg MF, et al. Telomere length is a determinant of emphysema susceptibility. American Journal of Respiratory and Critical Care

Medicine. 2011;**184**:904-912

[22] Molina-Molina M, Borie R. Clinical implications of telomere dysfunction in lung fibrosis. Current Opinion in Pulmonary Medicine.

2018;**24**(5):440-444

[21] Stanley SE, Merck SJ, Armanios M. Telomerase and genetics of

emphysema susceptibility. Implications for pathogenesis paradigms and patient care. Annals of the American Thoracic Society. 2016;**13**(Suppl 5):S447-S451

[23] Hruban RH, Meziane MA, Zerhouni EA, et al. High resolution computerized tomography of inflation-fixed lungs. Pathologic-radiologic correlation of centrilobular emphysema. The American Review of Respiratory Disease. 1987;**136**:935-940

[24] Miller RR, Muller NL, Vedal S, Morrison NJ, Staples CA. Limitations of computed tomography in the

SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest.

2017;**8**(3):153-165

2012;**141**:222-231

[17] Yousem SA. Respiratory

#### *Emphysema DOI: http://dx.doi.org/10.5772/intechopen.83273*

[17] Yousem SA. Respiratory bronchiolitis-associated interstitial lung disease with fibrosis is a lesion distinct from fibrotic nonspecific interstitial pneumonia: a proposal. Modern Pathology. 2006;(11):1474-1479

[18] Jelic TM, Estalilla OC, Sawyer-Kaplan PR, Plata MJ, Powers JT, Emmett M, et al. Coal mine dust desquamative chronic interstitial pneumonia: A precursor of dust-related diffuse fibrosis and of emphysema. International Journal of Occupational and Environmental Medicine. 2017;**8**(3):153-165

[19] Jankowich MD, Rounds SI. Combined pulmonary fibrosis and emphysema syndrome: a review. Chest. 2012;**141**:222-231

[20] Alder JK, Guo N, Parry EM, Anderson CJ, Gorgy AI, Walshg MF, et al. Telomere length is a determinant of emphysema susceptibility. American Journal of Respiratory and Critical Care Medicine. 2011;**184**:904-912

[21] Stanley SE, Merck SJ, Armanios M. Telomerase and genetics of emphysema susceptibility. Implications for pathogenesis paradigms and patient care. Annals of the American Thoracic Society. 2016;**13**(Suppl 5):S447-S451

[22] Molina-Molina M, Borie R. Clinical implications of telomere dysfunction in lung fibrosis. Current Opinion in Pulmonary Medicine. 2018;**24**(5):440-444

[23] Hruban RH, Meziane MA, Zerhouni EA, et al. High resolution computerized tomography of inflation-fixed lungs. Pathologic-radiologic correlation of centrilobular emphysema. The American Review of Respiratory Disease. 1987;**136**:935-940

[24] Miller RR, Muller NL, Vedal S, Morrison NJ, Staples CA. Limitations of computed tomography in the

assessment of emphysema. The American Review of Respiratory Disease. 1989;**139**:980-983

[25] Gulsen A. Bronchoscopic lung volume reduction: A 2018 review and update. Turkish Thoracic Journal. 2018;**19**(3):141-149

**48**

*Update in Respiratory Diseases*

Hill; 2005. pp. 1547-1554

[1] Reilly J, Silverman E, Shapiro S. Chronic obstructive pulmonary disease. In: Kasper D, Fauci A, Longo D, Braunwald E, Hauser S, Jameson LJ, editors. Harrison's Principles of Internal Medicine. 16th ed. New York: McGrawemphysema, its production with papain in normal and silicotic rats. Archives of Environmental Health. 1965;**11**:50-58

[9] Sethi S, Rochesert CL. Smoking and chronic obstructive pulmonary disease. Clinics in Chest Medicine.

[10] Hongwei Y, Rahman I. Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease. Toxicology and Applied Pharmacology.

[11] Church DF, Pryor WA. Freeradical chemistry of cigarette smoke and its toxicological implications. Environmental Health Perspectives.

[12] Tran I, Ji C, Ni I, Min T, Tang D, Vij N. Role of cigarette smoke-induced aggresome formation in chronic obstructive pulmonary diseaseemphysema pathogenesis. American Journal of Respiratory Cell and Molecular Biology. 2015;**53**(2):159-173

[13] Cohen RA, Petsonk EL, Rose C, et al. Lung pathology in U.S. coal workers with rapidly progressive pneumoconiosis implicates silica and silicates. American Journal of Respiratory and Critical Care

[14] Churg A, Zay K, Li K. Mechanisms of mineral dust-induced emphysema. Environmental Health Perspectives.

[15] Schns RP, Borm PJ. Mechanisms and mediators in coal dust induced toxicity: a review. The Annals of Occupational

Medicine. 1964;(6):673-680

1997;**105**(Suppl *5*):1215-1218

Hygiene. 1999;**43**(1):7-33

[16] Vassalllo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Seminars in Respiratory and Critical Care Medicine. 2008;**29**(6):643-650

2000;**21**:67-86

2011;**254**(2):72-85

1985;**64**:111-126

[2] Sorokin SP. The respiratory system. In: Weiss L, editor. Cell and Tissue Biology. 6th ed. Baltimore: Urban & Schwarzenberg; 1988. pp. 753-814

[3] Travis W, Colby T, Koss M, de Christenson R, Muller N, King T Jr. Non-Neoplastic Disorders of the Lower Respiratory Tract. Atlas of Nontumor Pathology. AFIP, ARP. pp. 435-471

[4] Schmidt RA, Glenny RW, Godwin JD, Hampson NB, Cantino ME, Reichenbach DD. Panlobular emphysema in young intravenous Ritalin abusers. The American Review of Respiratory Disease.

[5] Snider GL, Kleinerman J, Thurlbeck WM, Bengali ZH. The definition of emphysema. Report of a National Heart , Lung, and Blood Institute, Division of Lung Diseases workshop. The American

Review of Respiratory Disease.

[7] Laurell CB, Eriksson S. The electrophoretical alpha1-globulin pattern of serum alpha1-antitrypsin deficiency. Scandinavian Journal of Clinical and Laboratory Investigation.

[8] Gross P, Pfitzer EA, Tolker E, Babyok MA, Kaschak M. Experimental

[6] Pardo A, Selman M. Proteinaseantiproteinase imbalance in the pathogenesis of Emphysema: The role of metalloproteinases in lung damage. Histology and Histopathology.

1991;**143**:649-646

1985;**132**:182-185

1999;**14**:227-233

1963;**15**:132-140

**References**

**Chapter 4**

**Abstract**

*Stefan-Marian Frent*

biomarkers, eosinophils

**1. Introduction**

**51**

COPD Pharmacological

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. Although it is considered both preventable and treatable, COPD still represents an important public health challenge. The classes of pharmacological agents widely used for the maintenance treatment are bronchodilators (SABA, SAMA, LABA, LAMA) and inhaled corticosteroids (ICS). While it is largely accepted that inhaled bronchodilators, which are effective and well tolerated in patients with stable disease, are the cornerstone of the pharmacological management of COPD, there is an ongoing debate regarding the role of inhaled corticosteroids. This is also reflected in the last versions of the GOLD recommendations, which suffered dramatic changes in the recent years. The trend for personalized medicine led to the search for biomarkers which could guide the therapeutic decisions. Recent studies demonstrated that blood eosinophils can reasonably predict the ICS relative efficacy in preventing

COPD exacerbations and thus could inform the disease management.

infections (HIV, tuberculosis) [13, 14], and socioeconomic status [15].

trapping and chronic airflow limitation [1].

**Keywords:** COPD, lung function, exacerbation, bronchodilators, corticosteroids,

Chronic Obstructive Pulmonary Disease (COPD) is a common condition, usually affecting people of >40 years of age significantly exposed to noxious particles or gases [1]. Although considered both preventable and treatable [1], COPD remains a leading cause of morbidity and mortality [2, 3], affecting an estimated 384 million people worldwide [4]. The COPD prevalence is projected to increase in the coming decades [5], as well as its position among the leading causes of mortality [4]. Active or passive cigarette smoking is the most commonly encountered risk factor for COPD across the world [1]; however other factors may play a role in the disease pathogenesis, such as genetic factors [6, 7], exposure to indoor and outdoor air pollutants [8–11], exposure to occupational dusts, chemical agents or fumes [12],

The normal lung response to the inhalation of noxious factors is an inflammatory reaction of the airways. In patients who develop COPD, the excessive inflammatory response is further enhanced by the oxidative stress and an imbalance of the protease-antiprotease system, leading to the destruction of the lung parenchyma and disruption of normal repair and defense mechanisms. Emphysema and small airway fibrosis are the consequences of these processes, which translate into gas

Management Update

## **Chapter 4**
