**Nature and Consequences of the Systemic Inflammatory Response Induced by Lung Inflammation**

Kunihiko Hiraiwa and Stephan F. van Eeden

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57392

## **1. Introduction**

Lung inflammation is the basis for the majority of acute and chronic lung conditions. Acute lung injury (ALI) caused by either communicable (such as infection) or non-communicable (such as acid aspiration) diseases are characterized by a rapidly induced inflammatory response in the lung. There are numerous causes for ALI, as the lung is exposed to external factors either via the airways (infectious agents and environmental pollutants) or via the blood stream (sepsis, endotoxin, fat) and, when severe, can lead to acute respiratory distress syndrome (ARDS), a spectrum of lung diseases characterized by a severe inflammatory process in the lung parenchyma causing diffuse alveolar damage and respiratory failure [1, 2]. This acute inflammatory response in the lung is strongly associated with a systemic inflammatory response that may lead to multiple organ dysfunction and is associated with high mortality [3]. Similarly, chronic inflammatory lung conditions such as chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis and interstitial lung diseases, especially those associated with collagen vascular disease, have in recent years also been shown to be accom‐ panied by a systemic inflammatory response, albeit different in nature [4-14]. In addition, the systemic response induced by chronic lung inflammation is also associated with downstream adverse effects on different organ systems. This chapter will focus on defining the nature and features of this systemic response as a consequence of lung inflammation and will focus predominantly on chronic inflammatory lung conditions.

## **2. Lung conditions associated with a systemic inflammatory response**

Numerous lung conditions, especially inflammatory lung conditions, are known to be associated with a systemic inflammatory response. Although the associations and consequen‐

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ces of the systemic response in acute lung injury and inflammation have been well established [1, 2, 15], the associations in chronic inflammatory lung conditions are less well known. This chapter will discuss the current knowledge surrounding inflammatory lung conditions and their associations with a systemic response.

significantly. Host defects may be attributed to prior corticosteroid treatment, protein-calorie malnutrition or even genetic make-up, for example. The systemic response is characterized by activation of the coagulation cascade, complement proteins and the acute phase response.

Nature and Consequences of the Systemic Inflammatory Response Induced by Lung Inflammation

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Activation of cellular elements of blood such as platelets, granulocytes and mast cells cause degranulation and release of potent proinflammatory contents systemically, resulting in the systemic unleashing of otherwise beneficial local effects, leading to significant adverse effects

Since the 1970's and 1980's, the importance and consequences of the systemic response following acute lung inflammation have been recognized and well described, however, the systemic inflammatory response in chronic inflammatory lung conditions has only been recognized within the last ten years. The consequences and significance of this "lower grade" systemic response has only recently been more clearly defined. The chronic systemic inflam‐ matory response in the lung is characterized by mobilization and activation of inflammatory cells into the circulation, the production of acute phase proteins and an increase in circulating inflammatory mediators. Of all the chronic inflammatory lung conditions, the systemic

An integral component of the systemic inflammatory response is the stimulation of the hematopoietic system, specifically the bone marrow, which results in the release of leukocytes and platelets into the circulation. Large population-based studies have shown that the magnitude of the leukocytic response is a predictor of total mortality, independ‐

Chronic cigarette smoking increases circulating leukocyte numbers [25, 26], including imma‐ ture neutrophils, and results in high levels of myeloperoxidase and α1-antitrypsin, the latter a natural inhibitor of serine proteases and responsible for alveolar wall damage [27, 28], suggesting that the systemic response feeds back to the lung and perpetuates the lung

The acute phase response is an early and key part of the systemic component of the innate immune response and C-reactive protein (CRP) is a robust marker of this response. Subjects with severe airflow obstruction are more likely to have elevated CRP-levels and, in addition, high CRP levels have been related directly to severity of COPD and the associated systemic

Local anti-inflammatory therapy (inhaled corticosteroids) reduces circulating CRP whereas withdrawal of inhaled corticosteroids results in a significant increase in CRP levels [33], suggesting that lung inflammation drives the CRP levels in the blood of subjects with COPD. Moreover, CRP levels increase further during COPD exacerbations when lung inflammation flares up [33]. The increased circulating levels of CRP in COPD are associated with other mediators such as IL-6, which is the predominant cytokine regulator of CRP production by

inflammation, independent of cigarette smoking and coronary artery disease [29-32].

responses and consequences have been best characterized in COPD.

on multiple extra-pulmonary organs.

**2.2. Chronic lung inflammation**

ent of smoking [22-24].

inflammatory response.

hepatocytes.

#### **2.1. Acute lung inflammation**

The most recognized causes of acute lung inflammation are those induced either by infection or by direct or indirect ALI: for example, infections beginning in the lungs frequently transition into systemic events with hemodynamic effects (shock) and remote organ dysfunction such as acute kidney injury, which, when severe, may lead to death. Traditionally, the transition of infection from a localized event to one that is systemic in scope has been termed sepsis and is characterized by fever, tachycardia, tachypnea and a constellation of other signs and symp‐ toms indicating that the pathogen and the humoral events that accompany the infectious process, are now systemically distributed. Furthermore, a number of publications suggest that clinical events such as severe tissue injury and ischemia-reperfusion injury may also activate the systemic response of the host in a similar manner to sepsis [16, 17]. The recognition of this common pathophysiologic phenotype of the sepsis syndrome led to the term ''systemic inflammatory response syndrome'' or SIRS, characterized by global activation of the inflam‐ matory cascade, with an increase in circulating proinflammatory mediators leading to adverse downstream effects on numerous organ systems (so called multi-organ dysfunction). As mentioned, SIRS is an inflammatory response resulting from either local or systemic inflam‐ matory events which may be initiated by either infectious or non-infectious insults [18, 19].

The local acute inflammatory response in the lung is complex and involves activation of the innate immune response via binding of microbial products or cell injury-associated endoge‐ nous molecules (danger-associated molecular patterns [DAMPs]) to pattern recognition receptors such as the toll-like receptors on the lung epithelium and alveolar macrophages [20]. Complex autocrine and paracrine inter-relationships exist between cytokines and other proinflammatory mediators such as endothelial adhesion molecules that both initiate and amplify the inflammatory response. This is augmented further by the margination and migration of polymorphonuclear neutrophils (PMNs) and other humoral responses, both dependent or independent of the cells, such as lipid mediators, proteases, oxidants, growth factors (such as transforming growth factors [TGFs]), nitric oxide and neuropeptides [21]. Increased permeability of microvascular barriers results in extravascular accumulation of protein-rich edema fluid in airspaces, a cardinal feature of acute inflammation and a central pathophysiologic mechanism in ALI/ARDS.

The local inflammatory insult in the lung may exceed the efficiency of the inflammatory response to effectively contain it, resulting in inflammatory elements of either bacterial cell products and toxins or cellular alarmins, pathogen-associated molecular patterns (PAMPs) and other inflammatory elements of the local response to gain systemic access in sufficient quantity to activate the systemic inflammatory response.

The magnitude of the insult is not the sole determining factor for host failure to contain the inflammatory response: in some instances, defects in the hosts' responses may contribute significantly. Host defects may be attributed to prior corticosteroid treatment, protein-calorie malnutrition or even genetic make-up, for example. The systemic response is characterized by activation of the coagulation cascade, complement proteins and the acute phase response.

Activation of cellular elements of blood such as platelets, granulocytes and mast cells cause degranulation and release of potent proinflammatory contents systemically, resulting in the systemic unleashing of otherwise beneficial local effects, leading to significant adverse effects on multiple extra-pulmonary organs.

#### **2.2. Chronic lung inflammation**

ces of the systemic response in acute lung injury and inflammation have been well established [1, 2, 15], the associations in chronic inflammatory lung conditions are less well known. This chapter will discuss the current knowledge surrounding inflammatory lung conditions and

The most recognized causes of acute lung inflammation are those induced either by infection or by direct or indirect ALI: for example, infections beginning in the lungs frequently transition into systemic events with hemodynamic effects (shock) and remote organ dysfunction such as acute kidney injury, which, when severe, may lead to death. Traditionally, the transition of infection from a localized event to one that is systemic in scope has been termed sepsis and is characterized by fever, tachycardia, tachypnea and a constellation of other signs and symp‐ toms indicating that the pathogen and the humoral events that accompany the infectious process, are now systemically distributed. Furthermore, a number of publications suggest that clinical events such as severe tissue injury and ischemia-reperfusion injury may also activate the systemic response of the host in a similar manner to sepsis [16, 17]. The recognition of this common pathophysiologic phenotype of the sepsis syndrome led to the term ''systemic inflammatory response syndrome'' or SIRS, characterized by global activation of the inflam‐ matory cascade, with an increase in circulating proinflammatory mediators leading to adverse downstream effects on numerous organ systems (so called multi-organ dysfunction). As mentioned, SIRS is an inflammatory response resulting from either local or systemic inflam‐ matory events which may be initiated by either infectious or non-infectious insults [18, 19]. The local acute inflammatory response in the lung is complex and involves activation of the innate immune response via binding of microbial products or cell injury-associated endoge‐ nous molecules (danger-associated molecular patterns [DAMPs]) to pattern recognition receptors such as the toll-like receptors on the lung epithelium and alveolar macrophages [20]. Complex autocrine and paracrine inter-relationships exist between cytokines and other proinflammatory mediators such as endothelial adhesion molecules that both initiate and amplify the inflammatory response. This is augmented further by the margination and migration of polymorphonuclear neutrophils (PMNs) and other humoral responses, both dependent or independent of the cells, such as lipid mediators, proteases, oxidants, growth factors (such as transforming growth factors [TGFs]), nitric oxide and neuropeptides [21]. Increased permeability of microvascular barriers results in extravascular accumulation of protein-rich edema fluid in airspaces, a cardinal feature of acute inflammation and a central

The local inflammatory insult in the lung may exceed the efficiency of the inflammatory response to effectively contain it, resulting in inflammatory elements of either bacterial cell products and toxins or cellular alarmins, pathogen-associated molecular patterns (PAMPs) and other inflammatory elements of the local response to gain systemic access in sufficient

The magnitude of the insult is not the sole determining factor for host failure to contain the inflammatory response: in some instances, defects in the hosts' responses may contribute

their associations with a systemic response.

pathophysiologic mechanism in ALI/ARDS.

quantity to activate the systemic inflammatory response.

**2.1. Acute lung inflammation**

80 Lung Inflammation

Since the 1970's and 1980's, the importance and consequences of the systemic response following acute lung inflammation have been recognized and well described, however, the systemic inflammatory response in chronic inflammatory lung conditions has only been recognized within the last ten years. The consequences and significance of this "lower grade" systemic response has only recently been more clearly defined. The chronic systemic inflam‐ matory response in the lung is characterized by mobilization and activation of inflammatory cells into the circulation, the production of acute phase proteins and an increase in circulating inflammatory mediators. Of all the chronic inflammatory lung conditions, the systemic responses and consequences have been best characterized in COPD.

An integral component of the systemic inflammatory response is the stimulation of the hematopoietic system, specifically the bone marrow, which results in the release of leukocytes and platelets into the circulation. Large population-based studies have shown that the magnitude of the leukocytic response is a predictor of total mortality, independ‐ ent of smoking [22-24].

Chronic cigarette smoking increases circulating leukocyte numbers [25, 26], including imma‐ ture neutrophils, and results in high levels of myeloperoxidase and α1-antitrypsin, the latter a natural inhibitor of serine proteases and responsible for alveolar wall damage [27, 28], suggesting that the systemic response feeds back to the lung and perpetuates the lung inflammatory response.

The acute phase response is an early and key part of the systemic component of the innate immune response and C-reactive protein (CRP) is a robust marker of this response. Subjects with severe airflow obstruction are more likely to have elevated CRP-levels and, in addition, high CRP levels have been related directly to severity of COPD and the associated systemic inflammation, independent of cigarette smoking and coronary artery disease [29-32].

Local anti-inflammatory therapy (inhaled corticosteroids) reduces circulating CRP whereas withdrawal of inhaled corticosteroids results in a significant increase in CRP levels [33], suggesting that lung inflammation drives the CRP levels in the blood of subjects with COPD. Moreover, CRP levels increase further during COPD exacerbations when lung inflammation flares up [33]. The increased circulating levels of CRP in COPD are associated with other mediators such as IL-6, which is the predominant cytokine regulator of CRP production by hepatocytes.

Lastly, subjects with COPD have higher levels of several circulating proinflammatory medi‐ ators such as tumor necrosis factor (TNF)-α and its receptors (TNFR-55 and -75), which are associated with leukocyte activation and the concomitant weight loss in these subjects [34-39]. Levels of the proinflammatory mediators IL-6 and IL-8 have also been shown to increase systemically during acute exacerbations of COPD [40, 41] suggesting that exacerbation of lung inflammation fuels the systemic response.

systemic response to lung inflammation is an integral part of the disease and has important

Nature and Consequences of the Systemic Inflammatory Response Induced by Lung Inflammation

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**3. Lung cells contribute to the systemic inflammatory response induced by**

The cells lining the airways are mainly epithelial cells but also include alveolar macrophages and both cell types are exposed to the external environment. They are the first responders in the lung when the lung is exposed to external factors such as cigarette smoke, air pollutants or infectious agents. These cells are critically important in the processing and neutralization of inhaled environmental contaminants which include airborne particulate matter (PM), cigarette smoke, bacteria and viruses, shown in Figure 2. Alveolar macrophages are one of the most potent producers of inflammatory mediators in the lung. It is known that human alveolar macrophages exposed to PM10 (EHC-93) [46] are able to phagocytose these particles *in vivo* [43] and *in vitro* [45] and produce, in a dose-dependent manner, an array of mediators such as IL-1β, IL-6 and TNF-α that are part of the innate immune response. To test the contribution of the mediators produced by alveolar macrophages to the systemic response, supernatants from alveolar macrophages, incubated *ex vivo* with urban PM, were instilled into the lungs of rabbits. The supernatants produced a systemic bone-marrow stimulation response similar to that produced by direct deposition of urban PM into the rabbit lung [42, 43]. Analysis of the supernatants showed that the proinflammatory mediators IL-1β and IL-6, the chemokine macrophage inflammatory protein (MIP)-1α and granulocyte macrophage colony-stimulating factor (GM-CSF) are elevated when macrophages are incubated with urban PM [45]. Studies showing a strong relationship between the quantity of particles phagocytosed by macrophages in lung tissue and the magnitude of the systemic response, after urban PM exposure (Figure 3), support the notion that the production of inflammatory mediators by alveolar macrophages is important and suggests that alveolar macrophages are significant contributors to the innate

component of the systemic response following an inflammatory stimulus in the lung

Similar experiments using bronchial epithelial cells showed that, when exposed to urban PM, cells produce excess GM-CSF, IL-1β, IL-6, TNF-α, IL-8 and leukemia inhibitory factor (LIF) in a dose-dependent manner [47-49]. Some overlap was evident when comparing mediators produced by alveolar macrophages with those produced by bronchial epithelial cells after exposure to similar doses of urban PM, however, some distinct differences in the type and the magnitude of cytokine production was observed (Figure 4). The relative contributions of macrophages and epithelial cells in the production of mediators responsible for the systemic inflammatory response need to be determined. Alveolar macrophages are professional phagocytes and the magnitude of their cytokine production is significantly higher than bronchial epithelial cells, after the same level of exposure (Figure 4). These studies suggest that alveolar macrophages are key effector cells, responsible, at least, for generating the systemic inflammatory response associated with exposure to air pollution. However, although the macrophages are more potent producers of proinflammatory mediators expressed per cell basis, the airspace epithelial cells out-number the alveolar macrophages approximately ten

implications for disease pathogenesis and prognosis.

**lung inflammation**

Chronic obstructive pulmonary disease is predominantly caused when the lung is exposed to noxious particulate matter and gases from cigarette smoke. Lung inflammation induced by inhalation of other air pollutants such as particulate matter or PM10, nitric dioxide or ozone also causes a low grade inflammatory response in the lung. Experimental animal models exposed to ambient air pollutants [42, 43] and studies in humans [44, 45] have both shown that the inflammatory response in the lung induced by air pollutants is also associated with systemic inflammation, suggesting that the systemic response is not specific for cigarette smoke exposure (Figure 1).

**Figure 1.** Cytokines in the blood of subject during the Southeast Asia forest fires of 1997. The black bars represent the concentrations of cytokines in the serum during the haze period and the white bars after the haze cleared. Cytokine levels were higher during haze compared with after haze. Values are mean ± SEM of all samples with values within the detection limit of the assay (n = 30 per group).

Similar to lung inflammation caused by inhalation exposure, the systemic response has also been well documented in other inflammatory lung conditions such as asthma [4-7], suppura‐ tive lung conditions such as bronchiectasis [8, 9], interstitial lung disease (ILD), in particular, ILD associated with collagen vascular diseases such as lupus erythematosus, rheumatoid arthritis and scleroderma [10-14]. As stated previously, these chronic inflammatory lung conditions are associated with increased levels of acute phase proteins such as CRP, stimula‐ tion of the bone marrow with altered circulating leukocyte and platelets and increased circulating proinflammatory mediators. Extensive studies have been undertaken to identify potential biomarkers capable of predicting disease severity and prognosis, implying that the systemic response to lung inflammation is an integral part of the disease and has important implications for disease pathogenesis and prognosis.

Lastly, subjects with COPD have higher levels of several circulating proinflammatory medi‐ ators such as tumor necrosis factor (TNF)-α and its receptors (TNFR-55 and -75), which are associated with leukocyte activation and the concomitant weight loss in these subjects [34-39]. Levels of the proinflammatory mediators IL-6 and IL-8 have also been shown to increase systemically during acute exacerbations of COPD [40, 41] suggesting that exacerbation of lung

Chronic obstructive pulmonary disease is predominantly caused when the lung is exposed to noxious particulate matter and gases from cigarette smoke. Lung inflammation induced by inhalation of other air pollutants such as particulate matter or PM10, nitric dioxide or ozone also causes a low grade inflammatory response in the lung. Experimental animal models exposed to ambient air pollutants [42, 43] and studies in humans [44, 45] have both shown that the inflammatory response in the lung induced by air pollutants is also associated with systemic inflammation, suggesting that the systemic response is not specific for cigarette

**Figure 1.** Cytokines in the blood of subject during the Southeast Asia forest fires of 1997. The black bars represent the concentrations of cytokines in the serum during the haze period and the white bars after the haze cleared. Cytokine levels were higher during haze compared with after haze. Values are mean ± SEM of all samples with values within the

Similar to lung inflammation caused by inhalation exposure, the systemic response has also been well documented in other inflammatory lung conditions such as asthma [4-7], suppura‐ tive lung conditions such as bronchiectasis [8, 9], interstitial lung disease (ILD), in particular, ILD associated with collagen vascular diseases such as lupus erythematosus, rheumatoid arthritis and scleroderma [10-14]. As stated previously, these chronic inflammatory lung conditions are associated with increased levels of acute phase proteins such as CRP, stimula‐ tion of the bone marrow with altered circulating leukocyte and platelets and increased circulating proinflammatory mediators. Extensive studies have been undertaken to identify potential biomarkers capable of predicting disease severity and prognosis, implying that the

inflammation fuels the systemic response.

smoke exposure (Figure 1).

82 Lung Inflammation

detection limit of the assay (n = 30 per group).
