**4. Mediators of the systemic inflammatory response induced by lung inflammation**

Lung inflammation has been associated with an array of different circulating cellular or noncellular mediators that may differ significantly depending on the type and the character of the inflammatory response in the lung.

#### **4.1. Cellular components of the systemic response to lung inflammation**

induced bone marrow stimulation increases the population of younger PMN with a greater potential to damage tissue (Figure 5). This knowledge may be relevant to the pathogenesis of acute lung inflammation-induced adverse organ dysfunction in conditions such as sepsis, or the systemic adverse effects associated with chronic inflammatory lung conditions such as COPD. The immature leukocytes also tend to preferentially sequester in lung capillaries [65, 67] where they may further damage the lung and fuel lung inflammation, causing a vicious cycle of lung inflammation leading to systemic inflammation that feeds back, resulting in further lung inflammation (Figure 5). It is possible that the bone marrow stimulation associated with both acute and chronic inflammatory lung conditions contributes to the development of acute lung injury such as in ARDS as well as chronic lung injury promoting centrilobular

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

**Bacteria PM10 Smoke**

Alveolar space

**IL-8 TNF** 

**BONE MARROW**

**Figure 5.** Lung injury induced by immature PMNs. Alveolar macrophages and epithelial cells phagocytose bacteria, particulate matter or cigarette smoke and induce cytokine production. These cytokines spill over into the circulation and stimulate the bone marrow to recruit leukocytes. The newly recruited immature PMNs tend to preferentially se‐ quester in lung capillaries where they may be activated and degranulate, further damaging the lung. Lung damage

Common to nearly all inflammatory lung conditions are the production and release of mediators of the innate immune response. These circulating mediators, specifically the "acute response" cytokines IL-1β, IL-6 and TNF-α, activate the acute-phase response [68], by stimulating the liver to produce acute phase proteins, such as fibrinogen, that increas‐ es blood coagulability, which is a major risk factor for acute cardiovascular events in susceptible individuals [69]. Another acute-phase protein, CRP, is strongly associated with

**CD18**

Recruitment

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PMN

Alveolar macrophage

**IL-6 GM-CSF/G-SCF IL-8**

leads to excess cytokine production which further fuels the systemic inflammation.

**4.2. Non-cellular components of systemic response to lung inflammation**

Release of cytokines

Blood vessel

Phagocytosis

emphysema in susceptible subjects.

Figure 5

Increased circulating leukocyte counts, specifically granulocyte counts, have been used for decades as biomarkers of local inflammatory or infectious processes, including lung inflam‐ mation. Large population-based studies showing leukocytosis as a predictor of total mortality, independent of other risk factors such as cigarette smoking, underline the importance of increases in circulating leukocytes [23, 54, 55]. Therefore, an integral component of the systemic response to lung inflammation is the stimulation of the hematopoietic system, specifically the bone marrow, which results in an increase in circulating leukocytes. In humans, leukocyte increases caused by bone marrow stimulation can be identified and quantified by an increase in circulating immature granulocytes (band cells and metamyelocytes) [42], in contrast to increases in leukocyte counts induced by exercise or other cathecholamine stress that results largely in demargination of existing intravascular leukocytes [56]. When associated with lung inflammation, an increase in circulating band cells signifies that signals from the lung have activated and stimulated the bone marrow to release immature leukocytes. In humans both acute lung inflammation such as pneumonia [57] and chronic lung inflammation such as exposure to cigarette smoke or other air pollutants [44] have been shown to increase circulating band cells counts, implicating a systemic response that stimulates the bone marrow. In contrast, two separate studies of healthy subjects residing in regions with low particulate air pollution (such as the South Pole) for prolonged periods, showed that the circulating white blood cell (WBC) count fell below the normal range shortly after the subjects entered this pristine environment, remained low for the entire period that they were in this environment, and then returned to normal levels when they returned to the either the US [58] or Japan [59]. The Japanese study also showed that the fall in circulating leukocytes was associated with a fall in the number of circulating band cells, indicating a reduction in bone marrow output [59]. These studies suggest that the reductions in circulating WBC and band cell counts are the result of a reduction in bone marrow stimulation initiated by signals generated in the lung. To more accurately quantify the bone marrow response to lung inflammation, one group has developed a method to label precursor cells in the marrow with the thymidine analogue 5'bromo-2 deoxyuridine (BrdU) [60-62], allowing accurate identification of newly released leukocytes from the bone marrow and simplifying functional studies. Using this method they demon‐ strated that acute lung inflammation caused by a focal infection [61], as well as chronic lung inflammation induced by either cigarette smoke or urban air pollutants [27, 42, 63, 64], stimulate the bone marrow and accelerates the transit times of granulocytes and monocytes through the marrow, releasing them into the circulating pool of leukocytes. The ability to follow these labeled cells in the circulation allowed study of cell behavior and functional capability whereby this group was able to show preferential sequestration of younger PMNs in the gravity independent lung regions of animals exposed to cigarette smoke [63] and less efficient migration into inflammatory sites, compared to more mature cells [65, 66]. *In vitro* studies support these findings, showing that younger PMNs released from the bone marrow are less deformable and less chemotactic than mature PMNs already in the circulation [67].

Collectively, these studies have established that the circulating blood contains granulocytes such as neutrophils of varying ages and functional capabilities and that lung inflammationinduced bone marrow stimulation increases the population of younger PMN with a greater potential to damage tissue (Figure 5). This knowledge may be relevant to the pathogenesis of acute lung inflammation-induced adverse organ dysfunction in conditions such as sepsis, or the systemic adverse effects associated with chronic inflammatory lung conditions such as COPD. The immature leukocytes also tend to preferentially sequester in lung capillaries [65, 67] where they may further damage the lung and fuel lung inflammation, causing a vicious cycle of lung inflammation leading to systemic inflammation that feeds back, resulting in further lung inflammation (Figure 5). It is possible that the bone marrow stimulation associated with both acute and chronic inflammatory lung conditions contributes to the development of acute lung injury such as in ARDS as well as chronic lung injury promoting centrilobular emphysema in susceptible subjects.

Figure 5

**4.1. Cellular components of the systemic response to lung inflammation**

86 Lung Inflammation

Increased circulating leukocyte counts, specifically granulocyte counts, have been used for decades as biomarkers of local inflammatory or infectious processes, including lung inflam‐ mation. Large population-based studies showing leukocytosis as a predictor of total mortality, independent of other risk factors such as cigarette smoking, underline the importance of increases in circulating leukocytes [23, 54, 55]. Therefore, an integral component of the systemic response to lung inflammation is the stimulation of the hematopoietic system, specifically the bone marrow, which results in an increase in circulating leukocytes. In humans, leukocyte increases caused by bone marrow stimulation can be identified and quantified by an increase in circulating immature granulocytes (band cells and metamyelocytes) [42], in contrast to increases in leukocyte counts induced by exercise or other cathecholamine stress that results largely in demargination of existing intravascular leukocytes [56]. When associated with lung inflammation, an increase in circulating band cells signifies that signals from the lung have activated and stimulated the bone marrow to release immature leukocytes. In humans both acute lung inflammation such as pneumonia [57] and chronic lung inflammation such as exposure to cigarette smoke or other air pollutants [44] have been shown to increase circulating band cells counts, implicating a systemic response that stimulates the bone marrow. In contrast, two separate studies of healthy subjects residing in regions with low particulate air pollution (such as the South Pole) for prolonged periods, showed that the circulating white blood cell (WBC) count fell below the normal range shortly after the subjects entered this pristine environment, remained low for the entire period that they were in this environment, and then returned to normal levels when they returned to the either the US [58] or Japan [59]. The Japanese study also showed that the fall in circulating leukocytes was associated with a fall in the number of circulating band cells, indicating a reduction in bone marrow output [59]. These studies suggest that the reductions in circulating WBC and band cell counts are the result of a reduction in bone marrow stimulation initiated by signals generated in the lung. To more accurately quantify the bone marrow response to lung inflammation, one group has developed a method to label precursor cells in the marrow with the thymidine analogue 5'bromo-2 deoxyuridine (BrdU) [60-62], allowing accurate identification of newly released leukocytes from the bone marrow and simplifying functional studies. Using this method they demon‐ strated that acute lung inflammation caused by a focal infection [61], as well as chronic lung inflammation induced by either cigarette smoke or urban air pollutants [27, 42, 63, 64], stimulate the bone marrow and accelerates the transit times of granulocytes and monocytes through the marrow, releasing them into the circulating pool of leukocytes. The ability to follow these labeled cells in the circulation allowed study of cell behavior and functional capability whereby this group was able to show preferential sequestration of younger PMNs in the gravity independent lung regions of animals exposed to cigarette smoke [63] and less efficient migration into inflammatory sites, compared to more mature cells [65, 66]. *In vitro* studies support these findings, showing that younger PMNs released from the bone marrow are less deformable and less chemotactic than mature PMNs already in the circulation [67].

Collectively, these studies have established that the circulating blood contains granulocytes such as neutrophils of varying ages and functional capabilities and that lung inflammation-

**Figure 5.** Lung injury induced by immature PMNs. Alveolar macrophages and epithelial cells phagocytose bacteria, particulate matter or cigarette smoke and induce cytokine production. These cytokines spill over into the circulation and stimulate the bone marrow to recruit leukocytes. The newly recruited immature PMNs tend to preferentially se‐ quester in lung capillaries where they may be activated and degranulate, further damaging the lung. Lung damage leads to excess cytokine production which further fuels the systemic inflammation.

#### **4.2. Non-cellular components of systemic response to lung inflammation**

Common to nearly all inflammatory lung conditions are the production and release of mediators of the innate immune response. These circulating mediators, specifically the "acute response" cytokines IL-1β, IL-6 and TNF-α, activate the acute-phase response [68], by stimulating the liver to produce acute phase proteins, such as fibrinogen, that increas‐ es blood coagulability, which is a major risk factor for acute cardiovascular events in susceptible individuals [69]. Another acute-phase protein, CRP, is strongly associated with

inflammation in general but, in epidemiological studies, has also been correlated with the extent of atherosclerosis and heart disease [29, 70]. C-reactive protein has become the hallmark biomarker indicative of the extent and severity of cardiovascular disease [71-73] as well as many other systemic inflammatory conditions, for example auto-immune collagen vascular diseases such as rheumatoid arthritis and lupus erythematosus. The acute response is a specific, well-orchestrated sequence of events, characterized by an early release of the "alarm" cytokines IL-1β and TNF-α, followed by a second wave of cytokines (IL-8, IL-6, monocyte chemotactic protein [MCP]-1 and MIP-1α ) and growth factors such as GM-CSF and G-CSF. The second wave of cytokines produced in the lung is of particular importance in inducing the systemic inflammatory response. Granulocyte macrophage colony-stimulating factor is a hematopoietic growth factor that stimulates granulocyte and monocyte differentiation and release from the bone marrow, activates circulating leuko‐ cytes such as neutrophils and prolongs leukocyte survival in the circulation and tissues [74]. In addition, GM-CSF has also recently been identified as an important granulocyte deganulation factor that may enhance tissue damage induced by granulocytes [75]. One of the "acute response" cytokines that induces cytokine production by many cells is IL-1β, which is known to stimulate hematopoiesis, activate endothelial cells, induce the acutephase response and is pyrogenic [76]. Similarly, IL-6 stimulates hepatocytes to produce acute phase proteins, including CRP, fibrinogen and antiproteases [77], stimulates hemato‐ poiesis, specifically the production of platelets and has a broad stimulating effect on B- and T-cells. In addition, IL-6 activates the bone marrow, accelerates the transit time of granulo‐ cytes through the bone marrow promotes their release into the circulation and increases their sequestration in microvascular beds [78]. All the acute-phase response cytokines are proinflammatory in nature and suppress the production of anti-inflammatory cytokines such as IL-10, in fact, low circulating levels of this cytokine have been associated with a poor outcome in sepsis [79, 80]. Collectively, the acute response cytokines have the ability to elicit a systemic inflammatory response in response to lung inflammation that is characterized by an increase in circulating leukocytes, platelets and pro-inflammatory and prothrombotic mediators. In addition, cytokines also have the ability to activate circulat‐ ing leukocytes and platelets, as well as vascular endothelium, to promote leukocyte– endothelial adhesion and migration into tissues.

Moreover, they have been documented at sites of inflammation [83, 84] and increased numbers of circulating MPs have been reported in systemic diseases such as autoimmune collagen vascular disorders, atherosclerosis, hypercoagulability states, disseminating malignancies and infection, among others [85, 86]. Circulating endothelial MPs are associated with activated, damaged or stressed endothelial cells and are biomarkers of vascular injury. Microparticles may also remotely induce endothelial dysfunction by altering the intracellular production of vasorelaxing molecules such as nitric oxide and contribu‐ ting to the recruitment of leukocytes at the remote site [81, 87, 88]. Recently, MPs have been shown to increase during inflammatory lung conditions such as COPD [89] and increase further during acute COPD exacerbations [90]. Furthermore, subjects with autoimmune collagen vascular disorders with lung involvement have increased levels of circulating endothelial MPs [91], suggesting that MPs are not just useful biomarkers of lung inflamma‐ tion, but may play a critically important role in the pathogenesis of the downstream adverse

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effects that lung inflammation appears to have on distant organs.

associated with lung inflammation.

**5. Mechanisms of lung inflammation-induced systemic inflammation**

Several mechanisms have been postulated to explain the association of lung inflammation with the systemic inflammatory response (Figure 6). The hypothesis with the most supporting experimental evidence postulates that inflammatory mediators generated in lung tissue translocate into the circulation. As the lung receives substantial cardiac output, it is reasonable to suppose that small molecules may translocate from lung tissue to the blood stream, following a natural gradient, a process that may be augmented by increases in capillary permeability which often accompanies the lung inflammatory process. It has been suggested that a gradient of the acute proinflammatory mediator, elastase, and its natural inhibitor, α1-anti-trypsin, forms across the lung during acute neutrophilic lung inflamma‐ tion [92] and "spills over" into the systemic circulation. Recent studies from another group has confirmed these findings in experimental models of acute (lipopolysaccharides [LPS] induced) and chronic (air pollution-induced) lung inflammation [93, 94], supporting the hypothesis that the lung *per se* contribute directly to the systemic inflammatory response

There is also some evidence indicating that triggers of lung inflammation, such as ultrafine particulate matter, LPS and other bacterial toxins, translocate from the airspaces to the bloodstream [84, 95-97], either directly contributing to the systemic response or stimulating circulating immune cells such as monocytes to produce proinflammatory mediators that contribute to the systemic response. Collectively, there is ample evidence that small molecules or particles have the ability to directly translocate from the lung into the blood stream, generating a systemic inflammatory response. This is a particularly important mechanism if vascular permeability is compromised during the lung inflammatory response because it will

accelerate the systemic inflammatory response caused by lung inflammation.

Part of the lung injury or initial stress insult in the lung is the formation and release of microparticles (MP), which are small vesicles (0.1–1 mm in diameter) containing cell membrane, that are released by a variety of cells types following either activation or an insult such as oxidative stress [81]. Platelets, endothelial cells, leukocytes, erythrocytes and tumor cells are cell types prone to MP shedding. Microparticles are composed of cell membranes, with receptors, enclosing cytosolic components, including enzymes, transcrip‐ tion factors, mRNA and microRNA, all derived from the parent cell. Microparticles contain signaling elements that may activate receptors on target cells and may also bind to target cells and transfer part of their contents [82]. Moreover, because MPs circulate, they not only act on their local environment but also on sites far from their origin, thereby serving as a cell-to-cell communication network. Microparticles are known to affect inflammation, coagulation, endothelial function, cell survival, and intercellular communication [81].

Moreover, they have been documented at sites of inflammation [83, 84] and increased numbers of circulating MPs have been reported in systemic diseases such as autoimmune collagen vascular disorders, atherosclerosis, hypercoagulability states, disseminating malignancies and infection, among others [85, 86]. Circulating endothelial MPs are associated with activated, damaged or stressed endothelial cells and are biomarkers of vascular injury. Microparticles may also remotely induce endothelial dysfunction by altering the intracellular production of vasorelaxing molecules such as nitric oxide and contribu‐ ting to the recruitment of leukocytes at the remote site [81, 87, 88]. Recently, MPs have been shown to increase during inflammatory lung conditions such as COPD [89] and increase further during acute COPD exacerbations [90]. Furthermore, subjects with autoimmune collagen vascular disorders with lung involvement have increased levels of circulating endothelial MPs [91], suggesting that MPs are not just useful biomarkers of lung inflamma‐ tion, but may play a critically important role in the pathogenesis of the downstream adverse effects that lung inflammation appears to have on distant organs.

inflammation in general but, in epidemiological studies, has also been correlated with the extent of atherosclerosis and heart disease [29, 70]. C-reactive protein has become the hallmark biomarker indicative of the extent and severity of cardiovascular disease [71-73] as well as many other systemic inflammatory conditions, for example auto-immune collagen vascular diseases such as rheumatoid arthritis and lupus erythematosus. The acute response is a specific, well-orchestrated sequence of events, characterized by an early release of the "alarm" cytokines IL-1β and TNF-α, followed by a second wave of cytokines (IL-8, IL-6, monocyte chemotactic protein [MCP]-1 and MIP-1α ) and growth factors such as GM-CSF and G-CSF. The second wave of cytokines produced in the lung is of particular importance in inducing the systemic inflammatory response. Granulocyte macrophage colony-stimulating factor is a hematopoietic growth factor that stimulates granulocyte and monocyte differentiation and release from the bone marrow, activates circulating leuko‐ cytes such as neutrophils and prolongs leukocyte survival in the circulation and tissues [74]. In addition, GM-CSF has also recently been identified as an important granulocyte deganulation factor that may enhance tissue damage induced by granulocytes [75]. One of the "acute response" cytokines that induces cytokine production by many cells is IL-1β, which is known to stimulate hematopoiesis, activate endothelial cells, induce the acutephase response and is pyrogenic [76]. Similarly, IL-6 stimulates hepatocytes to produce acute phase proteins, including CRP, fibrinogen and antiproteases [77], stimulates hemato‐ poiesis, specifically the production of platelets and has a broad stimulating effect on B- and T-cells. In addition, IL-6 activates the bone marrow, accelerates the transit time of granulo‐ cytes through the bone marrow promotes their release into the circulation and increases their sequestration in microvascular beds [78]. All the acute-phase response cytokines are proinflammatory in nature and suppress the production of anti-inflammatory cytokines such as IL-10, in fact, low circulating levels of this cytokine have been associated with a poor outcome in sepsis [79, 80]. Collectively, the acute response cytokines have the ability to elicit a systemic inflammatory response in response to lung inflammation that is characterized by an increase in circulating leukocytes, platelets and pro-inflammatory and prothrombotic mediators. In addition, cytokines also have the ability to activate circulat‐ ing leukocytes and platelets, as well as vascular endothelium, to promote leukocyte–

Part of the lung injury or initial stress insult in the lung is the formation and release of microparticles (MP), which are small vesicles (0.1–1 mm in diameter) containing cell membrane, that are released by a variety of cells types following either activation or an insult such as oxidative stress [81]. Platelets, endothelial cells, leukocytes, erythrocytes and tumor cells are cell types prone to MP shedding. Microparticles are composed of cell membranes, with receptors, enclosing cytosolic components, including enzymes, transcrip‐ tion factors, mRNA and microRNA, all derived from the parent cell. Microparticles contain signaling elements that may activate receptors on target cells and may also bind to target cells and transfer part of their contents [82]. Moreover, because MPs circulate, they not only act on their local environment but also on sites far from their origin, thereby serving as a cell-to-cell communication network. Microparticles are known to affect inflammation, coagulation, endothelial function, cell survival, and intercellular communication [81].

endothelial adhesion and migration into tissues.

88 Lung Inflammation

#### **5. Mechanisms of lung inflammation-induced systemic inflammation**

Several mechanisms have been postulated to explain the association of lung inflammation with the systemic inflammatory response (Figure 6). The hypothesis with the most supporting experimental evidence postulates that inflammatory mediators generated in lung tissue translocate into the circulation. As the lung receives substantial cardiac output, it is reasonable to suppose that small molecules may translocate from lung tissue to the blood stream, following a natural gradient, a process that may be augmented by increases in capillary permeability which often accompanies the lung inflammatory process. It has been suggested that a gradient of the acute proinflammatory mediator, elastase, and its natural inhibitor, α1-anti-trypsin, forms across the lung during acute neutrophilic lung inflamma‐ tion [92] and "spills over" into the systemic circulation. Recent studies from another group has confirmed these findings in experimental models of acute (lipopolysaccharides [LPS] induced) and chronic (air pollution-induced) lung inflammation [93, 94], supporting the hypothesis that the lung *per se* contribute directly to the systemic inflammatory response associated with lung inflammation.

There is also some evidence indicating that triggers of lung inflammation, such as ultrafine particulate matter, LPS and other bacterial toxins, translocate from the airspaces to the bloodstream [84, 95-97], either directly contributing to the systemic response or stimulating circulating immune cells such as monocytes to produce proinflammatory mediators that contribute to the systemic response. Collectively, there is ample evidence that small molecules or particles have the ability to directly translocate from the lung into the blood stream, generating a systemic inflammatory response. This is a particularly important mechanism if vascular permeability is compromised during the lung inflammatory response because it will accelerate the systemic inflammatory response caused by lung inflammation.

vulnerable to microvascular dysfunction are the kidney, liver, brain and the gastrointestinal system. Containing the lung inflammatory response is critically important in order to inhibit progression to a systemic inflammatory response fueled by the vicious cycle of increased cytokine production and cellular damage, underlining the importance of lung inflammation

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

Circulating cytokines produced in the lung activate the vascular endothelium and this activation is associated with increased expression of several adhesion proteins such as ICAM-1, VCAM-1 and E-selectin. Both soluble ICAM-1 and VCAM-1 are upregulated in circulating blood during chronic inflammation and are correlated with increased disease in coronary and carotid arteries in humans. Support of these observations comes from animal models that have shown instillation of atmospheric particles into the lungs of rabbits [99] and mice [100] results in development of atherosclerosis, followed by rapid progression of the atherosclerotic process over the surface of the aorta with concomitant destabilization of existing atherosclerotic plaques (Figure 7). Furthermore, particulate deposition in murine lungs is associated with upregulation of both ICAM-1 and VCAM-1 on the endothelium overlying the atherosclerotic plaques [101]. In addition, the number of particle-phagocytosing alveolar macrophages shows a strong positive association with the extent of atherosclerosis (Figure 8), as well as with markers of systemic inflammation such as CRP [102]. These studies demonstrate that lung inflammation stimulates alveolar macrophages, increases circulating markers of inflamma‐ tion, increases endothelial activation and dysfunction and suggests a cause and effect rela‐ tionship between lung inflammation and the development and progression of vascular

as the primary "driver" for the downstream multiple organ dysfunction.

**5.2. Chronic lung inflammation and vascular dysfunction**

PM10 (n = 10) 4(11%) 5(14%)

**Figure 7.** The severity of atherosclerotic lesions in the aorta. Results shown in rabbits exposed to PM10 for four weeks (n = 10) or saline (controls; n = 6). The classification is based on the guidelines of the American Heart Association (AHA) [163, 164]. PM10 exposure was associated with progression to more advanced phenotypes of atherosclerosis

14(39%)

11(31%)

2(6%)

Control (n = 6)

4(17%) 1(4%) 5(21%)

11(46%)

3(13%)

type V type IV type III type II type I negative

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diseases such as atherosclerosis.

Figure 7

0

compared with the control group.

20

40

60

Classification of atherosclerotic lesions (%)

80

100

**Figure 6.** Impact of pulmonary inflammation on distant organ systems. Inflammatory mediators generated in the lung "spill over" into the circulation, activating the liver to release acute-phase proteins and the bone marrow to release leukocytes and platelets. Together, these circulating effector proteins and cells promote vascular disease and may pre‐ cipitate acute vascular events. Systemic inflammation also enhances lung inflammation by promoting the recruitment of immune cells into lung tissues.

#### **5.1. Feedback of downstream effects of the systemic response to acute lung inflammation**

Bacterial or viral lung infections are common causes of acute lung inflammation that lead to ALI/ARDS [1]. During the past decade, novel and highly virulent respiratory viruses such as the Severe Acute Respiratory Syndrome Coronavirus (SARS CoV) and highly pathogenic strains of influenza viruses have emerged as important causes of excessive lung damage in infected humans. Acute lung injury and associated inflammation frequently have systemic manifestations, coined the "systemic inflammatory response syndrome (SIRS)". Many patients with refractory ALI/ARDS succumb to multiple organ failure (MOF) rather than respiratory failure, underlining the importance of the systemic response to lung injury. Many studies have been undertaken to investigate the cellular or molecular mechanisms of acute lung injuryinduced systemic manifestations [1, 2, 15]. The deterioration from ALI/ARDS to MOF involves many steps, including the activation of multiple inflammatory pathways, increased expression of chemoattractants which results in endothelial changes and the release of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α, margination and migration of neutrophils as well as systemic activation of monocytes, all contributing to diffuse microvascular injury which is thought to lead to multi-organ injury and eventual failure [98]. Currently it is thought that the pivotal injury occurs to the vascular endothelium, leading to increased vascular permeability, which is then followed by translocation of inflammatory mediators and activated leukocytes into organ tissue resulting in organ inflammation and, finally, dysfunction. Organs particular vulnerable to microvascular dysfunction are the kidney, liver, brain and the gastrointestinal system. Containing the lung inflammatory response is critically important in order to inhibit progression to a systemic inflammatory response fueled by the vicious cycle of increased cytokine production and cellular damage, underlining the importance of lung inflammation as the primary "driver" for the downstream multiple organ dysfunction.

#### **5.2. Chronic lung inflammation and vascular dysfunction**

**5.1. Feedback of downstream effects of the systemic response to acute lung inflammation**

of immune cells into lung tissues.

90 Lung Inflammation

**Figure 6.** Impact of pulmonary inflammation on distant organ systems. Inflammatory mediators generated in the lung "spill over" into the circulation, activating the liver to release acute-phase proteins and the bone marrow to release leukocytes and platelets. Together, these circulating effector proteins and cells promote vascular disease and may pre‐ cipitate acute vascular events. Systemic inflammation also enhances lung inflammation by promoting the recruitment

Bacterial or viral lung infections are common causes of acute lung inflammation that lead to ALI/ARDS [1]. During the past decade, novel and highly virulent respiratory viruses such as the Severe Acute Respiratory Syndrome Coronavirus (SARS CoV) and highly pathogenic strains of influenza viruses have emerged as important causes of excessive lung damage in infected humans. Acute lung injury and associated inflammation frequently have systemic manifestations, coined the "systemic inflammatory response syndrome (SIRS)". Many patients with refractory ALI/ARDS succumb to multiple organ failure (MOF) rather than respiratory failure, underlining the importance of the systemic response to lung injury. Many studies have been undertaken to investigate the cellular or molecular mechanisms of acute lung injuryinduced systemic manifestations [1, 2, 15]. The deterioration from ALI/ARDS to MOF involves many steps, including the activation of multiple inflammatory pathways, increased expression of chemoattractants which results in endothelial changes and the release of proinflammatory cytokines such as IL-1β, IL-6 and TNF-α, margination and migration of neutrophils as well as systemic activation of monocytes, all contributing to diffuse microvascular injury which is thought to lead to multi-organ injury and eventual failure [98]. Currently it is thought that the pivotal injury occurs to the vascular endothelium, leading to increased vascular permeability, which is then followed by translocation of inflammatory mediators and activated leukocytes into organ tissue resulting in organ inflammation and, finally, dysfunction. Organs particular Circulating cytokines produced in the lung activate the vascular endothelium and this activation is associated with increased expression of several adhesion proteins such as ICAM-1, VCAM-1 and E-selectin. Both soluble ICAM-1 and VCAM-1 are upregulated in circulating blood during chronic inflammation and are correlated with increased disease in coronary and carotid arteries in humans. Support of these observations comes from animal models that have shown instillation of atmospheric particles into the lungs of rabbits [99] and mice [100] results in development of atherosclerosis, followed by rapid progression of the atherosclerotic process over the surface of the aorta with concomitant destabilization of existing atherosclerotic plaques (Figure 7). Furthermore, particulate deposition in murine lungs is associated with upregulation of both ICAM-1 and VCAM-1 on the endothelium overlying the atherosclerotic plaques [101]. In addition, the number of particle-phagocytosing alveolar macrophages shows a strong positive association with the extent of atherosclerosis (Figure 8), as well as with markers of systemic inflammation such as CRP [102]. These studies demonstrate that lung inflammation stimulates alveolar macrophages, increases circulating markers of inflamma‐ tion, increases endothelial activation and dysfunction and suggests a cause and effect rela‐ tionship between lung inflammation and the development and progression of vascular diseases such as atherosclerosis. Figure 7

**Figure 7.** The severity of atherosclerotic lesions in the aorta. Results shown in rabbits exposed to PM10 for four weeks (n = 10) or saline (controls; n = 6). The classification is based on the guidelines of the American Heart Association (AHA) [163, 164]. PM10 exposure was associated with progression to more advanced phenotypes of atherosclerosis compared with the control group.

sclerotic vascular disease [99-102]. Activation of coronary vasculature by the systemic response to COPD lung inflammation also impacts other vascular beds such as the cerebral vascular bed. Circulating inflammatory mediators such as IL-1β, IL-6, TNF-α, α1-antichymotrypsin and TNFR1 are associated with cognitive decline, either through a direct neurotoxic effect or through cerebral atherosclerosis effects [108, 109]. Figure 9 highlights potential pathways of blood vessel activation due to systemic inflammation in COPD that results in endothelial dysfunction and destabilization of atherosclerotic plaques, possibly leading to vascular events

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**Figure 9.** Impact of lung injury on blood vessels. Circulating mediators such as IL-6 induce the release of CRP and fibri‐ nogen from the liver. In addition, IL-6 and GM-CSF stimulate the bone marrow to release leukocytes and platelets, while TNF-α and IL-1β activate vascular endothelial cells and upregulate endothelial ICAM-1 and VCAM-1, thereby promoting the recruitment of monocytes into blood vessel walls. Activation of endothelial cells also increases endo‐ thelial permeability, promotes uptake of oxidized low-density lipoproteins (oxLDL) into vessel walls, promotes the re‐ lease of endothelin-1 (ET-1) and decreases availability of nitric oxide (NO). Together, these changes in blood vessel walls lead to endothelial dysfunction and promote vulnerability of atherosclerotic plaques to rupture, possibly leading

Cachexia and muscle wasting are hallmarks of COPD, especially in subjects with severe disease and, currently, the mechanisms underlying these downstream effects of COPD are a topic of active investigation. In COPD subjects, skeletal muscle shows increased apoptosis, increased oxidative stress and increased inflammatory cell infiltration [110, 111], suggesting that inflammatory processes play a role in the physiologic changes seen in skeletal muscles of COPD subjects. Furthermore, the underlying inflammatory and oxidative processes in the lungs, in addition to the downstream proinflammatory systemic responses, shifts the hormo‐

such as acute coronary syndrome and stroke.

to acute cardiac events or strokes.

**Figure 8.** The correlation between the percentage of alveolar macrophages that phagocytosed particles in the lung and the vol/vol (volume fraction) of atherosclerotic lesions in the left main coronary artery (LMCA) and right coronary artery (RCA). Results shown in rabbits exposed to PM10 for four weeks (solid circles; n = 10) or saline (controls; open circles; n = 6). The volume fraction (vol/vol) of atherosclerosis was determined by point counting the sections. The cor‐ relation between variables were examined by the Spearman rank correlation test (r = 0.53, p < 0.05) [99].

#### **5.3. Systemic inflammation in COPD**

Numerous studies have established that COPD is associated with a low-grade systemic inflammatory response, which has been implicated in the pathogenesis of the majority of the systemic effects associated with COPD, including muscle weakness, weight loss, cardiovas‐ cular disease, depression, diabetes and osteoporosis [103]. Patients with stable COPD have increased numbers of circulating leukocytes, increased levels of acute phase response proteins (CRP and fibrinogen) and increased cytokine levels (IL-6 and TNF-α) [104] that increase further with acute exacerbations [105, 106].

Chronic obstructive pulmonary disease is a chronic inflammatory condition of the airways and lung parenchyma caused predominantly by the inhalation of toxic particles and noxious gasses, with cigarette smoking contributing to the bulk of the disease burden. There is a strong association between cardiovascular disease and COPD morbidity and mortality. Cardiovas‐ cular events are the predominant reason for hospitalizations (morbidity) and a leading cause of mortality in subjects with mild and moderate COPD [107]. Furthermore, epidemiological studies have shown that compromised lung function (FEV1) in subjects with COPD is associated with cardiovascular morbidity and mortality, even after controlling for smoking history [107], suggesting that the inflammatory response in the lung which causes the reduced lung function also impacts the vasculature. The mechanisms of COPD-induced cardiovascular disease are still unclear, however, animals models of cigarette exposure or exposure to ambient particulate matter suggest that the systemic response induced by these inhalation stimuli causes vascular dysfunction that may promote the development and progression of athero‐ sclerotic vascular disease [99-102]. Activation of coronary vasculature by the systemic response to COPD lung inflammation also impacts other vascular beds such as the cerebral vascular bed. Circulating inflammatory mediators such as IL-1β, IL-6, TNF-α, α1-antichymotrypsin and TNFR1 are associated with cognitive decline, either through a direct neurotoxic effect or through cerebral atherosclerosis effects [108, 109]. Figure 9 highlights potential pathways of blood vessel activation due to systemic inflammation in COPD that results in endothelial dysfunction and destabilization of atherosclerotic plaques, possibly leading to vascular events such as acute coronary syndrome and stroke.

**5.3. Systemic inflammation in COPD**

Figure 8

92 Lung Inflammation

Volume fraction of atherosclerotic

lesions in LMCA and RCA (%)

0

10

20

30

40

50

60

with acute exacerbations [105, 106].

Numerous studies have established that COPD is associated with a low-grade systemic inflammatory response, which has been implicated in the pathogenesis of the majority of the systemic effects associated with COPD, including muscle weakness, weight loss, cardiovas‐ cular disease, depression, diabetes and osteoporosis [103]. Patients with stable COPD have increased numbers of circulating leukocytes, increased levels of acute phase response proteins (CRP and fibrinogen) and increased cytokine levels (IL-6 and TNF-α) [104] that increase further

**Figure 8.** The correlation between the percentage of alveolar macrophages that phagocytosed particles in the lung and the vol/vol (volume fraction) of atherosclerotic lesions in the left main coronary artery (LMCA) and right coronary artery (RCA). Results shown in rabbits exposed to PM10 for four weeks (solid circles; n = 10) or saline (controls; open circles; n = 6). The volume fraction (vol/vol) of atherosclerosis was determined by point counting the sections. The cor‐

relation between variables were examined by the Spearman rank correlation test (r = 0.53, p < 0.05) [99].

alveolar macrophages phagocytosedparticles (%)

PM Control (n = 6) <sup>10</sup> (n = 10)

0 20 40 60 80 100

Y=11.0+0.29 X, r = 0.53, p < 0.05

Chronic obstructive pulmonary disease is a chronic inflammatory condition of the airways and lung parenchyma caused predominantly by the inhalation of toxic particles and noxious gasses, with cigarette smoking contributing to the bulk of the disease burden. There is a strong association between cardiovascular disease and COPD morbidity and mortality. Cardiovas‐ cular events are the predominant reason for hospitalizations (morbidity) and a leading cause of mortality in subjects with mild and moderate COPD [107]. Furthermore, epidemiological studies have shown that compromised lung function (FEV1) in subjects with COPD is associated with cardiovascular morbidity and mortality, even after controlling for smoking history [107], suggesting that the inflammatory response in the lung which causes the reduced lung function also impacts the vasculature. The mechanisms of COPD-induced cardiovascular disease are still unclear, however, animals models of cigarette exposure or exposure to ambient particulate matter suggest that the systemic response induced by these inhalation stimuli causes vascular dysfunction that may promote the development and progression of athero‐

**Figure 9.** Impact of lung injury on blood vessels. Circulating mediators such as IL-6 induce the release of CRP and fibri‐ nogen from the liver. In addition, IL-6 and GM-CSF stimulate the bone marrow to release leukocytes and platelets, while TNF-α and IL-1β activate vascular endothelial cells and upregulate endothelial ICAM-1 and VCAM-1, thereby promoting the recruitment of monocytes into blood vessel walls. Activation of endothelial cells also increases endo‐ thelial permeability, promotes uptake of oxidized low-density lipoproteins (oxLDL) into vessel walls, promotes the re‐ lease of endothelin-1 (ET-1) and decreases availability of nitric oxide (NO). Together, these changes in blood vessel walls lead to endothelial dysfunction and promote vulnerability of atherosclerotic plaques to rupture, possibly leading to acute cardiac events or strokes.

Cachexia and muscle wasting are hallmarks of COPD, especially in subjects with severe disease and, currently, the mechanisms underlying these downstream effects of COPD are a topic of active investigation. In COPD subjects, skeletal muscle shows increased apoptosis, increased oxidative stress and increased inflammatory cell infiltration [110, 111], suggesting that inflammatory processes play a role in the physiologic changes seen in skeletal muscles of COPD subjects. Furthermore, the underlying inflammatory and oxidative processes in the lungs, in addition to the downstream proinflammatory systemic responses, shifts the hormo‐ nal balance towards catabolism, reducing testosterone levels and increasing catecholamine synthesis, especially in the severe stages of the disease (FEV1<30%) [112]. It is reasonable to postulate that the systemic inflammatory response associated with COPD lung inflammation contributes to the skeletal muscle inflammation and concomitant muscle wasting seen in COPD.

Patients afflicted with lung injury more commonly than not encounter more than 'one-hit' modulating the immunological response to injury by increasing duration and amplitude of the inflammatory response [127]. In animal models, the traditional "single-hit" model is no longer considered a good approximation of human ALI/ARDS, whereas a "two-hit" model has been shown to increase the inflammatory response in the lung [127-130]. This "priming" phenomenon may be pivotal in subjects with chronic lung inflammation, such as COPD, where the systemic inflammatory response induced by the chronic lung inflammation may feed-back, aggravating the lung inflammatory response. This vicious cycle of inflammation promoting further inflammation may be the reason why subjects with COPD still have active lung inflammation many years after they have stopped smoking [131]. This phenomenon is also seen in patients with asthma, where, even years after cessation of exposure, patients with Western red cedar-initiated asthma have persistent airflow obstruction [132]. In this study, higher impairment was associated with serum IFN-γ (Figure 10), which supports the hypoth‐ esis of a vicious cycle of inflammation with crosstalk between the lung and systemic inflam‐

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

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

95

Figure 10 p = 0.04

Impairment class (IC)

**Figure 10.** Serum interferon-gamma, stratified by higher (2/3) versus lower (0/1) respiratory impairment (IC = impair‐ ment class). The blood samples were collected from 40 non-smoking male at a mean interval of 25 years from cedar asthma diagnosis and 17 years from last cedar exposure. The respiratory impairment class was defined by ATS guide‐ lines [165]. Asthma-related respiratory impairment was associated with higher interferon-gamma levels in serum

(n = 24) (n = 16)

Serrum

(average 1.32 pg/ml for IC2/3 versus average 0.62 pg/ml for IC0/1; p = 0.04) [132].

interferon-gamma (pg/ml)

matory responses.

Both diabetes mellitus type2 and osteoporosis are associated with COPD, especially in subjects with greater disease severity [113-115]. The mechanisms underlying the former two diseases are complex but a postulated mechanisms linking them with COPD is the presence of elevated circulating levels of proinflammatory mediators such as IL-1β, IL-6 and TNF-α. Therefore it seems reasonable to postulate that the systemic response in COPD may either aggravate or enhance the development of osteoporosis and diabetes, to a certain extent.

#### **5.4. Systemic inflammation in other inflammatory lung conditions**

Asthma is predominantly an inflammatory condition of the airways, however a systemic inflammatory response has also been well documented, evidenced by an increase in circulating proinflammatory cytokines such as IL-6 and TNF-α that stimulate hepatic production of acutephase proteins such as CRP, as well as an increase in immune cells such as neutrophils and eosinophils [4, 116]. Circulating TNF-α and IL-6 levels are further elevated during asthma exacerbation [117, 118]. Downstream consequences of this systemic response are less well studied and are insufficiently understood, therefore require further investigation. Similarly, interstitial lung disease and fibrosis are a large group of inflammatory lung conditions that include chronic hypersensitivity pneumonitis, sarcoidosis, drug-induced lung disease, lung disease associated with collagen vascular disease, idiopathic pulmonary fibrosis (IPF) and more. Many of these lung conditions are associated with increased circulating levels of proinflammatory mediators such as IL-1β, IL-6, TNF-α, TGF-β and platelet-derived growth factor (PDGF) [119, 120]. In conditions that exclusively involve the lung such as hypersensitivity pneumonitis and IPF, translocation of these mediators from the lung into the circulation may be responsible for the measured systemic response, however the effect of these mediators on other organ systems are unclear and require further study.

#### **5.5. Effect of the systemic inflammatory response on lung inflammation**

It is well known that non-pulmonary disorders (for example sepsis, trauma, massive transfu‐ sion, drug overdose, pancreatitis) cause lung injury and inflammation. "Crosstalk" between lungs and distal organs is an emerging, interesting and clinically relevant field [121, 122]. A complex network of cytokines, as well as proinflammatory chemokines such as CXCL1, from distant organs can initiate and amplify the lung injury [123, 124]. Many of the mediators involved in the systemic response have the ability to both damage lungs directly and stimulate the bone marrow to release leukocytes into the circulation. In addition, leukocytes that may have been sequestered in the lung could be released, potentially causing additional lung injury [125, 126]. These newly released leukocytes, specifically granulocytes such as neutrophils, have been shown to be preferentially sequestered in the pulmonary capillary bed where, if activated, they may contribute to further lung injury and damage [65, 66].

Patients afflicted with lung injury more commonly than not encounter more than 'one-hit' modulating the immunological response to injury by increasing duration and amplitude of the inflammatory response [127]. In animal models, the traditional "single-hit" model is no longer considered a good approximation of human ALI/ARDS, whereas a "two-hit" model has been shown to increase the inflammatory response in the lung [127-130]. This "priming" phenomenon may be pivotal in subjects with chronic lung inflammation, such as COPD, where the systemic inflammatory response induced by the chronic lung inflammation may feed-back, aggravating the lung inflammatory response. This vicious cycle of inflammation promoting further inflammation may be the reason why subjects with COPD still have active lung inflammation many years after they have stopped smoking [131]. This phenomenon is also seen in patients with asthma, where, even years after cessation of exposure, patients with Western red cedar-initiated asthma have persistent airflow obstruction [132]. In this study, higher impairment was associated with serum IFN-γ (Figure 10), which supports the hypoth‐ esis of a vicious cycle of inflammation with crosstalk between the lung and systemic inflam‐ matory responses.

nal balance towards catabolism, reducing testosterone levels and increasing catecholamine synthesis, especially in the severe stages of the disease (FEV1<30%) [112]. It is reasonable to postulate that the systemic inflammatory response associated with COPD lung inflammation contributes to the skeletal muscle inflammation and concomitant muscle wasting seen in

Both diabetes mellitus type2 and osteoporosis are associated with COPD, especially in subjects with greater disease severity [113-115]. The mechanisms underlying the former two diseases are complex but a postulated mechanisms linking them with COPD is the presence of elevated circulating levels of proinflammatory mediators such as IL-1β, IL-6 and TNF-α. Therefore it seems reasonable to postulate that the systemic response in COPD may either aggravate or

Asthma is predominantly an inflammatory condition of the airways, however a systemic inflammatory response has also been well documented, evidenced by an increase in circulating proinflammatory cytokines such as IL-6 and TNF-α that stimulate hepatic production of acutephase proteins such as CRP, as well as an increase in immune cells such as neutrophils and eosinophils [4, 116]. Circulating TNF-α and IL-6 levels are further elevated during asthma exacerbation [117, 118]. Downstream consequences of this systemic response are less well studied and are insufficiently understood, therefore require further investigation. Similarly, interstitial lung disease and fibrosis are a large group of inflammatory lung conditions that include chronic hypersensitivity pneumonitis, sarcoidosis, drug-induced lung disease, lung disease associated with collagen vascular disease, idiopathic pulmonary fibrosis (IPF) and more. Many of these lung conditions are associated with increased circulating levels of proinflammatory mediators such as IL-1β, IL-6, TNF-α, TGF-β and platelet-derived growth factor (PDGF) [119, 120]. In conditions that exclusively involve the lung such as hypersensitivity pneumonitis and IPF, translocation of these mediators from the lung into the circulation may be responsible for the measured systemic response, however the effect of these mediators on

enhance the development of osteoporosis and diabetes, to a certain extent.

**5.4. Systemic inflammation in other inflammatory lung conditions**

other organ systems are unclear and require further study.

they may contribute to further lung injury and damage [65, 66].

**5.5. Effect of the systemic inflammatory response on lung inflammation**

It is well known that non-pulmonary disorders (for example sepsis, trauma, massive transfu‐ sion, drug overdose, pancreatitis) cause lung injury and inflammation. "Crosstalk" between lungs and distal organs is an emerging, interesting and clinically relevant field [121, 122]. A complex network of cytokines, as well as proinflammatory chemokines such as CXCL1, from distant organs can initiate and amplify the lung injury [123, 124]. Many of the mediators involved in the systemic response have the ability to both damage lungs directly and stimulate the bone marrow to release leukocytes into the circulation. In addition, leukocytes that may have been sequestered in the lung could be released, potentially causing additional lung injury [125, 126]. These newly released leukocytes, specifically granulocytes such as neutrophils, have been shown to be preferentially sequestered in the pulmonary capillary bed where, if activated,

COPD.

94 Lung Inflammation

**Figure 10.** Serum interferon-gamma, stratified by higher (2/3) versus lower (0/1) respiratory impairment (IC = impair‐ ment class). The blood samples were collected from 40 non-smoking male at a mean interval of 25 years from cedar asthma diagnosis and 17 years from last cedar exposure. The respiratory impairment class was defined by ATS guide‐ lines [165]. Asthma-related respiratory impairment was associated with higher interferon-gamma levels in serum (average 1.32 pg/ml for IC2/3 versus average 0.62 pg/ml for IC0/1; p = 0.04) [132].
