**6. COPD**

thelium increases and the neutrophil "crawls" in search of a suitable route to cross the vessel wall, either paracellular or transcellular. At this point the neutrophil extends pseudopodlike surface projections that penetrate the endothelium. Upon penetration the neutrophil in‐ creases expression of surface integrins and releases proteases that function to break through

Once in the interstitium, PMNs must target the specific site of infection amidst large number of healthy cells. This is accomplished by a two pronged method of sensing inflammatory chemoattractant gradients. PMNs sense a chemoattractant gradient of IL-8 produced by damaged host cells and resident monocyte/macrophages through CXCR1 and CXCR2 (both GPCRs), and also detect fMLP (FPR1 receptor) LPS (TLR4), flagellin (TLR5), through pattern recognition receptors. [18] Although PMNs have been traditionally thought to promulgate an active innate immunity with little regulation, more recent evidence suggests that PMNs carefully coordinate a well-tailored immune response. A classic example of this regulated coordination is the elegant response of PMNs to IL-8. [19] As PMNs travel along the IL-8 gradient activation and release of microbicidal molecules occurs in a step-wise manner. With increasing concentrations of IL-8, neutrophils first produce more β-integrins, subse‐ quently begin the oxidative burst, and finally degranulate potent proteases into the intracel‐ lular space. [20] The trafficking of neutrophils to sites of inflammation is with dual purpose: 1) to release their antimicrobial arsenal, and 2) to recruit more neutrophils and other innate

The neutrophil's arsenal includes the following weapons with which the neutrophil attacks pathogens: release of aforementioned granules with their anti-microbial contents, synthesis and release of anti-microbial peptides, production of reactive oxygen species (ROS) during the respiratory/oxidative burst, phagocytosis (mainly utilized to remove debris) and the re‐ lease of neutrophil extracellular traps (NETs), composed of DNA material that entraps in‐ vading pathogens. The second objective is accomplished through the release soluble mediators such as IL-12 and IFN-gamma that form a complex network of recruitment of oth‐ er neutrophils, dendritic cells, natural killer cells and macrophages. [21] Neutrophils can al‐ so act as antigen presenting cells in communication with CD8+ T cells, thus forming a link between innate and adaptive immunity. Such a potent response to injury and inflammation depends on negative feedback mechanisms, the short life span of neutrophils and the clear‐ ance of apoptotic neutrophils by macrophages. If left unchecked, the inflammatory response

Neutrophils are capable of responding to a number of inflammatory stimuli other than in‐ fection. Cigarette smoking has been shown to be a primary stimulus for the activation and migration of neutrophils into the tissues. Neutrophil treatment with cigarette smoke induces β2-integrin activation and firm adhesion to fibrinogen. Increased levels of neutrophil elas‐ tase, and matrix metalloproteases has been demonstrated with exposure to cigarette smoke. Furthermore, there is a decrease in superoxide production in the presence of cigarette smoke, indicating that smoking may lead to an impaired response to bacterial challenge.

It is with this potential for destructive dysregulation that we provide the following review of selected neutrophil mediated, inflammatory lung diseases. The definition, etiology, epi‐

(Fig. 1)

mediated by neutrophils can be a major contributor to chronic disease. 4

the vascular basement membrane and into the inflamed tissue. [16]

102 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

immune cells to the site of inflammation.

## **6.1. Overview and epidemiology**

Chronic obstructive pulmonary disease (COPD) is marked by progressive and irreversible airway limitation, chronic bronchitis, pulmonary hypertension and emphysema. These tis‐ sue changes are secondary to persistent, chronic pulmonary inflammation in response to persistent exposure to toxic gases or particles, primarily tobacco smoke. In addition to a baseline inflammatory state, the disease is associated with frequent exacerbations due to constant inflammation. [22],[23] Although preventable and treatable, COPD is a significant cause of morbidity and mortality worldwide. As the leading cause of pulmonary-related death in the world, COPD was the fifth leading cause of death worldwide in 2001 and is ex‐ pected to move to third by 2020. [24]

elastase (HNE), which degrade connective tissue, particularly elastin, of the alveolar wall, leading to emphysema. [31]-[33] Airway narrowing results from fibroblast proliferation and collagen deposition around the bronchioles in response to TGF Β (transforming growth fac‐

New Frontiers in the Diagnosis and Treatment of Chronic Neutrophilic Lung Diseases

http://dx.doi.org/10.5772/53834

105

Neutrophils themselves are a primary factor in the continuation of the pro-inflammatory state seen in COPD. The hypersecretion of mucus is linked to the accumulation of PMNs. Neutrophil elastase stimulates mucin gene expression; hence goblet cells and mucus glands produce excess mucus, leaving the bronchioles further obstructed. [34],[35] HNE is a one of a family of neutrophil serine proteases that have pluripotent effects in COPD. Not only can HNE degrade the basement membrane but it also directly affects ciliary beat frequency and cleaves CD2, CD4, and CD8 on T-cells, affecting their function. Additionally, HNE cleaves CXCR1 on PMNs, creating an impotent neutrophil that travels to the site of infection but is incapable of acting once it arrives. [36] Furthermore, other neutrophil proteins such as pro‐ tienase-3, cathepsin G, and myeloperoxidase are all pro-inflammatory molecules released by

The current standard for COPD diagnosis is spirometry. Lung spirometry measures the vol‐ ume of exhaled air, thus providing a functional assessment of airway obstruction. Two key spirometric values are FEV1 (forced expiratory volume), the volume of exhaled air over the first second of forced expiration, and FVC (forced vital capacity) or the total volume of air exhaled during forced expiration. These values are interpreted as a ratio (FEV1/FVC) where‐ by a decreasing value indicates increasing airway obstruction. A ratio less than 0.70 after bronchodilator treatment is diagnostic for COPD. [38],[39] Clinical indications for spiromet‐ ric evaluation include age greater than 40 years, family history of COPD, past exposure to

Pharmacological therapy of COPD is rooted in combating the symptoms that present sec‐ ondary to the tissue damage described above. Currently drug therapy is limited to a small cadre of drug classes. Therapeutic agents include bronchodilators, glucocorticoste‐ roids and phosphodiesterase inhibitors. Bronchodilators are the mainstay of COPD thera‐ py. Β 2 receptor agonists act on bronchial smooth muscle, promoting relaxation and airway dilation. Both long acting (daily therapy) and short acting (acute exacerbation) formulations are used. [40] Anticholinergics, or acetylcholine antagonists complement the airway dilating mechanism of β-agonists by blocking parasympathetic muscarinic recep‐ tors that otherwise cause bronchial smooth muscle contraction. [41] Inhaled glucocorti‐ costeroids aid in controlling inflammation, but are typically only used in conjunction with other drug classes. Oral, or systemic, glucocorticoid therapy is reserved for acute

inhaled irritants, chronic cough and sputum production and dyspnea. [22]

tor) released by macrophages and irritated epithelial cells.

**6.4. Role of neutrophils in COPD**

the neutrophil upon activation or necrosis. [37]

**6.5. Diagnosis of COPD**

**6.6. Traditional COPD therapeutics**

## **6.2. Etiology**

An overwhelming proportion of COPD is related directly to cigarette smoking. Other envi‐ ronmental irritants that have been implicated in the development of COPD include coal and metal mining dust, urban pollution, and indoor cooking with biofuels. [25] Irrespective of secondary irritants, greater than 90% of individuals diagnosed with COPD are current or former smokers. However, only a minority of current and former smokers develop sympto‐ matic COPD (15-20%), suggesting COPD is a confluence of environmental factors and genet‐ ic susceptibility. [26] The complex nature of the inflammatory process and its response to environmental factors in COPD confounds the search for individual susceptibility genes. [27] To that end, several genome-wide association studies (GWAS) have been performed with the goal of elucidating the genetic factors related COPD pathogenesis. Unfortunately, even in this current age of rapid whole genome sequencing, multiple GWAS studies have only postulated loose corollaries of genes and association with disease. No genes associated with COPD have displayed a Mendelian mode of inheritance with respect to causation of COPD. [28]

## **6.3. Pathophysiology**

On a cellular level, the pathophysiology of COPD is essentially a heightened, perpetually ac‐ tive inflammatory process. Inflammation is typically localized in the small airways and pa‐ renchyma of the lungs, where irritant molecules become trapped. The difference between the normal inflammatory cascade and that seen in COPD is the damage immune cells and their mediators inflict upon the lung tissues due to persistent activation. Lung function de‐ cline, characteristic of COPD, is linked to three distinct but synergistic mechanisms: destruc‐ tion of alveolar walls (emphysema), narrowing of the small airways, and hypersecretion of mucus. [29]

The inflammatory cascade leading to COPD is a complex interaction of immune cells and molecular mediators. The process begins with the inhalation of cigarette smoke or other chemical irritants, which damages the airway epithelium leading to release of chemoattrac‐ tant molecules. Cigarette smoke was also shown by Braber et al. to induce β2 integrin-de‐ pendant migration of neutrophils across endothelial cells. [30] These ligands bind and activate chemokine receptors on circulating neutrophils, helper T cells, cytotoxic T cells and monocytes and recruit them to the lungs. Monocytes migrate across the epithelium and dif‐ ferentiate, joining the resident macrophages. As the congregation of immune cells grows they release proteases, such as matrix metalloproteinase-9 (MMP-9) and human neutrophil elastase (HNE), which degrade connective tissue, particularly elastin, of the alveolar wall, leading to emphysema. [31]-[33] Airway narrowing results from fibroblast proliferation and collagen deposition around the bronchioles in response to TGF Β (transforming growth fac‐ tor) released by macrophages and irritated epithelial cells.

## **6.4. Role of neutrophils in COPD**

sue changes are secondary to persistent, chronic pulmonary inflammation in response to persistent exposure to toxic gases or particles, primarily tobacco smoke. In addition to a baseline inflammatory state, the disease is associated with frequent exacerbations due to constant inflammation. [22],[23] Although preventable and treatable, COPD is a significant cause of morbidity and mortality worldwide. As the leading cause of pulmonary-related death in the world, COPD was the fifth leading cause of death worldwide in 2001 and is ex‐

An overwhelming proportion of COPD is related directly to cigarette smoking. Other envi‐ ronmental irritants that have been implicated in the development of COPD include coal and metal mining dust, urban pollution, and indoor cooking with biofuels. [25] Irrespective of secondary irritants, greater than 90% of individuals diagnosed with COPD are current or former smokers. However, only a minority of current and former smokers develop sympto‐ matic COPD (15-20%), suggesting COPD is a confluence of environmental factors and genet‐ ic susceptibility. [26] The complex nature of the inflammatory process and its response to environmental factors in COPD confounds the search for individual susceptibility genes. [27] To that end, several genome-wide association studies (GWAS) have been performed with the goal of elucidating the genetic factors related COPD pathogenesis. Unfortunately, even in this current age of rapid whole genome sequencing, multiple GWAS studies have only postulated loose corollaries of genes and association with disease. No genes associated with COPD have displayed a Mendelian mode of inheritance with respect to causation of

On a cellular level, the pathophysiology of COPD is essentially a heightened, perpetually ac‐ tive inflammatory process. Inflammation is typically localized in the small airways and pa‐ renchyma of the lungs, where irritant molecules become trapped. The difference between the normal inflammatory cascade and that seen in COPD is the damage immune cells and their mediators inflict upon the lung tissues due to persistent activation. Lung function de‐ cline, characteristic of COPD, is linked to three distinct but synergistic mechanisms: destruc‐ tion of alveolar walls (emphysema), narrowing of the small airways, and hypersecretion of

The inflammatory cascade leading to COPD is a complex interaction of immune cells and molecular mediators. The process begins with the inhalation of cigarette smoke or other chemical irritants, which damages the airway epithelium leading to release of chemoattrac‐ tant molecules. Cigarette smoke was also shown by Braber et al. to induce β2 integrin-de‐ pendant migration of neutrophils across endothelial cells. [30] These ligands bind and activate chemokine receptors on circulating neutrophils, helper T cells, cytotoxic T cells and monocytes and recruit them to the lungs. Monocytes migrate across the epithelium and dif‐ ferentiate, joining the resident macrophages. As the congregation of immune cells grows they release proteases, such as matrix metalloproteinase-9 (MMP-9) and human neutrophil

pected to move to third by 2020. [24]

104 Oncogenesis, Inflammatory and Parasitic Tropical Diseases of the Lung

**6.2. Etiology**

COPD. [28]

mucus. [29]

**6.3. Pathophysiology**

Neutrophils themselves are a primary factor in the continuation of the pro-inflammatory state seen in COPD. The hypersecretion of mucus is linked to the accumulation of PMNs. Neutrophil elastase stimulates mucin gene expression; hence goblet cells and mucus glands produce excess mucus, leaving the bronchioles further obstructed. [34],[35] HNE is a one of a family of neutrophil serine proteases that have pluripotent effects in COPD. Not only can HNE degrade the basement membrane but it also directly affects ciliary beat frequency and cleaves CD2, CD4, and CD8 on T-cells, affecting their function. Additionally, HNE cleaves CXCR1 on PMNs, creating an impotent neutrophil that travels to the site of infection but is incapable of acting once it arrives. [36] Furthermore, other neutrophil proteins such as pro‐ tienase-3, cathepsin G, and myeloperoxidase are all pro-inflammatory molecules released by the neutrophil upon activation or necrosis. [37]
