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The Proceedings of the American Thoracic Society 2:61-67 (2005)
© 2005 The American Thoracic Society

Systemic Response to Ambient Particulate Matter

Relevance to Chronic Obstructive Pulmonary Disease

Stephan F. van Eeden, Adam Yeung, Kevin Quinlam and James C. Hogg

iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, Vancouver, British Columbia, Canada

Correspondence and requests for reprints should be addressed to Stephan F. van Eeden, M.D., Ph.D., iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC, V6Z1Y6 Canada. E-mail: svaneeden{at}mrl.ubc.ca


   ABSTRACT
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 ABSTRACT
LUNG INFLAMMATION CAUSES A...
 SUMMARY
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Chronic obstructive pulmonary disease (COPD) is a risk factor for development of cardiovascular events, independent of smoking. The mechanisms are unclear, but systemic inflammation associated with COPD may contribute to this cardiovascular risk. Similar to cigarette smoking, exposure to particulate air pollution is associated with an increase in the mortality and morbidity from respiratory and cardiovascular diseases. The exposure of humans to high levels of ambient particles stimulates the bone marrow and the release of neutrophils, band cells, and monocytes into the circulation. This bone marrow simulation is associated with increased levels of circulating interleukin-1ß and interleukin-6, similar to cigarette smoking. In animals, exposure to particulate matter accelerates the transit of neutrophils and monocytes in bone marrow and expands the leukocyte pool size. This systemic inflammatory response to particle inhalation causes endothelial activation and upregulation adhesion molecules that are critically important in leukocyte recruitment into atherosclerotic plaques. Exposure to particles also causes disease progression and destabilization of atherosclerotic plaques in rabbits that develop atherosclerosis naturally. We suspect, therefore, that the systemic inflammatory responses described activate vascular endothelium and cause progression and instability of atherosclerotic plaques. We speculate that this mechanism may contribute to the cardiovascular morbidity and mortality associated with COPD.

Key Words: air pollution • atherosclerosis • cigarette smoke • COPD • cytokines • leukocytes

Chronic obstructive pulmonary disease (COPD) is a condition characterized by chronic airway inflammation and remodeling, lung parenchymal inflammation, and destruction resulting in expiratory airflow obstruction, hyperinflation of the lung with loss of elastic recoil, and, ultimately, disturbance of gas exchange. Although cigarette smoking is the most important cause of COPD, air pollution, chronic lung infection, and genetic factors have all been implicated to contribute to or cause the syndrome. Epidemiologic studies have shown that reduced lung function in subjects with COPD is associated with cardiovascular morbidity and mortality, even after taking into account smoking history (1–4). The Lung Health Study reported that a 10% decrement in lung function (FEV1) among patients with COPD is associated with an approximate 30% increase in the risk of deaths from cardiovascular diseases that include thromboembolic disease, arrhythmias, heart failure, stroke, and sudden death (4–6). The mechanisms whereby COPD adversely affects the cardiovascular system are not known, but the low-grade systemic inflammatory response associated with COPD may contribute to the atherothrombotic cardiovascular disease in these patients.

Several studies have shown that such a low-grade systemic inflammation is present in subjects with COPD (7–9). Patients with COPD have increased circulating levels of C-reactive protein (CRP), tumor necrosis factor (TNF)-{alpha} and its receptors, and interleukins (IL)-6 and IL-8, which all increase further during exacerbations (8). The systemic response in COPD has been implicated in the progression of lung disease and in the skeletal muscle wasting associated with advanced disease and the pathogenesis of coronary heart disease and atherosclerosis in subjects with COPD (8, 10).

We have shown that exposure to ambient air pollution particles also induced a low-grade systemic inflammatory response in both humans (11) and animals (12) and postulate that this systemic inflammation initiates the vascular effects in COPD. This supports the hypothesis proposed by Seaton and colleagues that deposition of particles in the lung provokes a low-grade alveolar inflammation that causes exacerbations of COPD and asthma and also increased blood coagulability resulting in cardiovascular deaths in susceptible individuals (13) This is supported by a recent study from Sunyer and colleagues (14) showing exposure to urban air pollution particles (and not gaseous pollutants) is an independent predictor for mortality in subjects admitted for COPD exacerbation. In the present review, we provide evidence for the systemic inflammatory response induced by exposure to atmospheric particles and cigarette smoke with particular reference to its effect on the bone marrow and blood vessels.


   LUNG INFLAMMATION CAUSES A SYSTEMIC INFLAMMATORY RESPONSE
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 LUNG INFLAMMATION CAUSES A...
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The systemic inflammatory response 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.

Lung Inflammation and Mobilization of Leukocytes
An integral component of the systemic inflammatory response is stimulation of the hematopoietic system, specifically the bone marrow, that results in the release of leukocytes and platelets into the circulation. The level of this leukocytosis was a predictor of total mortality, independent of smoking, in large population-based studies (11, 12, 15). Chronic cigarette smoking increases circulating leukocyte numbers (16, 17), including immature neutrophils with high levels of myeloperoxidase and {alpha}1-antitrypsin, a natural inhibitor of serine proteases responsible for alveolar wall damage (18, 19). Furthermore, studies from our laboratory have shown that humans exposed to atmospheric particles mobilize leukocytes into the circulation as part of the systemic response; this leukocytosis is associated with stimulation of the bone marrow (20). During the widespread forest fires in Southeast Asia in 1997, soldiers who performed exercise outdoors on a regular basis as part of their combat training developed a leukocytosis and an increase in circulating band cells indicative of a bone marrow response that returned to normal after the haze cleared (20). The predominant pollutant during the forest fires was particles, and their levels relate temporally to changes in band cell counts. In contrast, reports from the United States (21) and Japan (22) showed a sharp decrease in circulating leukocyte counts and band cells that persisted over several months in subjects residing in Antarctica, where particulate levels are very low because of low levels of combustion of fossil fuels. These subjects also showed a subsequent increase in leukocyte and band cell counts on their return to Japan, and the leukocyte counts throughout the study correlate with the measured particulate levels (22). These studies suggest that the bone marrow increases its output when the lung is challenged by increasing concentrations of atmospheric particles and suppresses its output when the lung is exposed to low levels of atmospheric particles (20, 22).

To quantify this bone marrow response, we have developed a technique to identify and quantify leukocytes released from a stimulated marrow by pulse-labeled precursors that divide in the marrow with the thymidine analog, 5'bromo-2-deoxyuridine (BrdU). This allows us to study the release of leukocytes from the marrow and calculate the effect of a marrow stimulus on their transit time through the different pools in the marrow (23, 24). Moreover, this technique allows us to calculate the size of the different pools of leukocytes in the marrow. Using this technique, we have shown in animals that cigarette smoking stimulates the bone marrow to release immature neutrophils (19) and that these neutrophils sequester preferentially in lung capillaries (25). Similarly, acute exposure to atmospheric particles causes an acceleration of the neutrophil transit time through the bone marrow pools particularly the maturation pool with the release of younger immature neutrophils into the circulation (26). In contrast, chronic exposure over a 4-week period predominately causes an increase in the size of the bone marrow pools (27) with very small changes in neutrophil transit times through the marrow.

Recently, we have extended these studies and showed that monocytes are released from bone marrow (28) at baseline earlier and more rapidly than neutrophils (Figure 1). The release of monocytes from the marrow was accelerated further by inflammation in the lung induced by infection (29) or atmospheric particles (30). These monocytes, newly released from the marrow, sequester preferentially at the inflammatory site and migrate into the airspaces after a period of intravascular maturation (29). Monocytes are progenitors for alveolar macrophages and are known to accumulate in the lung in response to cigarette smoke (31). These macrophages can be activated directly by cigarette smoke to release chemoattractants such as monocyte chemoattractant protein-1, a chemokine thought to be critically important in sustaining the chronic inflammation in the pulmonary tissues of patients with COPD (31, 32).



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  		Figure 1. The relation between the release of monocytes and neutrophils from the bone marrow. Dividing myelocytes in the bone marrow of New Zealand white rabbits were pulse-labeled with the thymidine analog 5'bromo-2-deoxyuridine (BrdU) and the release of labeled leukocytes in the circulation traced using immunocytochemistry staining for BrdU. Monocytes are released from the bone marrow more rapidly than neutrophils. The peak of release of monocytes are approximately 16 hours and neutrophils approximately 72 hours with the mean transit time of monocytes through the marrow 35.2 ± 0.9 hours versus 100.9 ± 2.6 hours for neutrophils (p < 0.001). Values are mean ± SE of monocytes (n = 6) and neutrophils (n = 5).

 
Lung Inflammation and Circulating Mediators
Increased circulating levels of inflammatory mediators have been documented in subjects with COPD (33). Increased levels of TNF-{alpha} and its receptors (TNFR-55 and -75) have been associated with activation of leukocytes (34, 35) and weight loss (9, 36). Elevated levels of IL-6 and IL-8 have also been shown (37), which increase further during exacerbations (8, 38). Nemmar and colleagues demonstrated an increase in thrombogenicity in hamsters exposed to diesel particles that was related possibly to histamine release into the circulation (39). Studies from our laboratory have shown increased levels of circulating IL-6 and IL-1ß in smokers without COPD (Figure 2). We also showed that subjects exposed to increased levels of ambient particles have elevated circulating cytokines levels such as IL-1ß, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF) (40). These circulating cytokines may be responsible for the marrow responses induced by lung inflammation. IL-8 (41), the hematopoietic growth factor, granulocyte colony-stimulating factor (42), and IL-6 (43) each have stimulating effects on the bone marrow and are likely candidate mediators of the bone marrow response associated with lung inflammation. IL-6 is one of the important mediators of the acute phase response, and we have shown that this cytokine also potently stimulates the bone marrow to release leukocytes and platelets (43, 44). IL-6 is also a permissive factor for monocytic colony formation by human hematopoietic progenitor cells (45), and may be an important proinflammatory cytokine responsible for the release of both neutrophils and monocytes from the marrow by lung inflammation.



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  		Figure 2. Circulating cytokines in healthy smokers. Serum cytokines were measured in healthy smokers (no symptoms and at least a 5-pack-year smoking history, n = 20) and compared with healthy never smokers (n = 12) matched for age and sex using a sensitive enzyme-linked immunosorbent assay (ELISA, from Dako). Both interleukin (IL)-6 (p < 0.002) and IL-1ß (p < 0.02) and interferon-{gamma} (p < 0.02, graph not shown) were significantly higher in smokers. Values are mean ± SE.

 
The major effect of IL-8 is to demarginate neutrophils from within the vascular space; this chemokine also releases immature neutrophil precursors into the circulation (41). These myeloid cells may play an important role in modulating the inflammatory response in the lung and blood vessels. The neutrophils released from the bone marrow by IL-6 (46) and granulocyte colony-stimulating factor (47) are less deformable and sequester preferentially in microvessels, where they have the ability to contribute to tissue inflammation distant from the sites of inflammation in the lung. GM-CSF is a hematopoietic growth factor that stimulates granulocyte and monocyte differentiation and release from the bone marrow, and activates circulating leukocytes and prolongs their survival in the circulation (48). GM-CSF has also been identified recently to be an important degranulation factor that may enhance tissue damage induced by granulocytes (49). IL-1ß is one of the "acute response" cytokines that induces cytokine production by many cells, stimulates hematopoiesis, activates endothelial cells, is pyrogenic, and induces the acute phase response (48). TNF-{alpha} and IL-1ß, together with IL-6, are responsible for the activation of the acute phase response (44). This response generates CRP, fibrinogen, and other coagulation factors that have all been associated with thromboembolic cardiovascular events (50–52). Collectively, GM-CSF, IL-1ß, and IL-6 have the ability to elicit a systemic inflammatory response characterized by an increase in circulating leukocytes, platelets, proinflammatory, and prothrombotic proteins. They also have the ability to activate circulating leukocytes and the endothelium of the vascular bed to promote leukocyte-endothelial adhesion and migration.

Cardiovascular Effects of the Systemic Inflammatory Response
The systemic response induced by lung inflammation may influence the progression of pre-existing diseases in distant organ systems. As noted earlier, population-based studies have shown that reduced lung function is associated with cardiovascular morbidity and mortality (1–4). Similarly, studies have shown an association between levels of ambient particles and increased cardiovascular morbidity and mortality (53–56). Cardiovascular events such as acute myocardial infarction, arrhythmias, and congestive heart failure cause the majority of air pollution–related hospital admissions and death. Schwartz and colleagues studied hospital admission for cardiovascular diseases in the Tucson valley (55) and showed a 2.75% increase in admissions for a 23 µg/m3 increase in suspended particles. These findings were supported by Peters and colleagues (57), who showed an increase in acute myocardial infarctions within 2 hours of an elevation of ambient particulate matter, PM2.5 (particles smaller than 2.5 µm). Seaton and colleagues proposed that an increase in blood coagulability induced by deposition of particles in the lung resulted in cardiovascular deaths in susceptible individuals (13). Nemmar and colleagues have shown platelet activation in hamsters exposed to diesel particles (58, 59), proposing that mediators generated in the lung are instrumental in this platelet activation. Our own work supports the concept that exposure to cigarette smoke or ambient particulate matter results in a systemic inflammatory response characterized by activation of the acute phase response with an increase blood coagulability, release of circulating inflammatory mediators that activate endothelium, and stimulation of the bone marrow to release leukocytes and platelets. Together, these events could contribute to destabilization of atherosclerotic plaques that make them vulnerable for rupture and thrombosis. Alternatively, very small particles (ultrafine particles) may translocate from the lung into the circulation and directly activate blood vessels, causing endothelial dysfunction, a key step in destabilization of atherosclerotic plaques. Oberdorster and colleagues have shown that ultrafine carbon particles translocate to organs such as the liver in rat exposure experiments (60), and Nemmar and colleagues showed that these intravascular translocated ultrafine particles are prothrombotic (58). They also showed that blood exposed to a very small amount of particles (0.5 µg/ml) shows significant platelet activation, suggesting that the prothrombotic effect induced by diesel particle exposure is most likely via at least two different mechanisms. Together these mechanisms may account for the increase cardiovascular events associated with episodes of air pollution (57), specifically in subjects with chronic lung inflammation such as in COPD.

Circulating cytokines activate the vascular endothelium and this activation is associated with an increased expression of von Willebrand factor, an endothelial glycoprotein involved in hemostasis (61), and the expression of the intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin (62). Both cell surface ICAM-1 and VCAM-1 are upregulated in endothelium stimulated with cytokines such as IL-1ß and TNF-{alpha}, and the levels of the soluble forms or these adhesion proteins in the blood correlates with the extent of disease in coronary and carotid arteries (62–64). Moreover, studies from our laboratories showed that instillation of atmospheric particles into the lungs of rabbits that develop atherosclerosis naturally upregulate both endothelial ICAM-1 and VCAM-1 (Figure 3) over plaques. This observation supports the notion that some stimuli that induce lung inflammation can also activate the vascular endothelium. These adhesion proteins are important for the recruitment of monocytes and lymphocytes into the atherosclerotic plaques. Endothelial activation also induces the production of nitric oxide and endothelin in vessel walls. Increased levels of circulating endothelin and tissue endothelin immunoreactivity have been documented in subjects with atherosclerosis and coronary artery disease (65). Animals exposed by inhalation to urban particulate matter have up to 100% elevated levels of endothelin as early as 2 hours after exposure, and the effect lasts as long as 2 days (66). This time course of elevated endothelin correlates well with the increase in acute coronary events associated with elevations in atmospheric particulate matter (57). Endothelin released from endothelial cells activates monocytes, is a potent vasoconstrictor, and influences the inflammatory response by modulating leukocyte-endothelial cell interactions, thereby promoting the recruitment of leukocytes into vessel walls. Together, these studies suggest that lung inflammation increases circulating markers of endothelial dysfunction, and may indicate a possible association between lung inflammation and the development of atherosclerosis.




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  		Figure 3. Expression of intercellular adhesion molecule (ICAM)-1 (A) and vascular cell adhesion molecule (VCAM)-1 (B) in the aortic tissue of Watanabe hereditarily hyperlipidemic (WHHL) rabbits after exposure to ambient particles. WHHL rabbits were exposed to ambient particles (EHC 93) for 4 weeks as previously described in detail (see ref. 72) and the expression of ICAM-1 and VCAM-1 measured (immunohistochemistry) and quantify (point counting on computer-generated, random-selected fields of view) on normal endothelium (no morphologic plaque) and over and in plaque tissue of the aorta. Both ICAM-1 and VCAM-1 (p < 0.05) were higher in plaque tissue (endothelium covering the plaques and in the intima) of particle exposed rabbits (n = 10) compared with control WHHL rabbits (n = 6). There were no differences in the expression of ICAM-1 and VCAM-1 on normal endothelium away from the plaque tissue. Values are mean ± SE and expressed as volume fractions (Vf) (example: 0.2 = 20% of surface area stained).

 
We have shown that an episode of acute air pollution increases circulating levels of IL-1ß and IL-6 (40). Biasucci and colleagues reported recently increased circulating levels of IL-1 receptor antagonist and IL-6 in subjects with unstable angina, and these high levels correlated with a complicated hospital course (67). These cytokines have the ability to activate endothelium, increase endothelial production of IL-8, upregulate endothelial adhesiveness, and promote the recruitment of leukocytes. Chemokines such as IL-8 can function as a chemoattractant for T-lymphocytes and monocytes (68) and stimulate smooth muscle cell proliferation and migration (69). An increase in IL-8 expression has also been associated with macrophage-rich regions in aortic aneurysms (68) and, as an angiogenic factor, is as potent as fibroblast growth factor and vascular endothelial growth factor. Angiogenesis and neovascularization in atherosclerotic plaques are associated with plaque instability and hemorrhage. This neovascularization develops preferentially in the intimal shoulder region of the plaque and is thought to supply this metabolically active region with blood and nutrients. This region is also a site for leukocyte trafficking and hemorrhage within the plaque that may lead to plaque instability (70). These studies illustrated the inflammatory nature of atherosclerosis and the importance of circulating cytokines and chemokines in this process.

Atherosclerosis is a multifactorial disease associated with risk factors that include cigarette smoking, hypertension, diabetes, and hyperlipidemia, particularly high levels of low-density lipoproteins. Studies both in animals and humans have established that the initiation and progression of atherosclerotic lesions is associated with endothelial activation (71–73). Circulating inflammatory mediators may activate endothelial cells and cause their dysfunction, an early and important step in the development of atherosclerosis. There is a growing body of evidence that inflammation is an integral component of atherogenesis. The inflammatory nature of atherosclerosis is further supported by studies showing an elevation of circulating acute phase proteins such as fibrinogen, CRP, and serum amyloid A in subjects with atherosclerosis, coronary artery disease, and unstable angina (51, 74). Peters and colleagues have linked changes in blood viscosity and activation of the acute phase response with particulate matter air pollution (52, 75). We have tested the hypothesis that the increased levels of circulating inflammatory mediators induced by breathing airborne particles causes progression and instability of atherosclerosis in animals that naturally develop atherosclerotic plaques (Watanabe hereditarily hyperlipidemic rabbits). These studies showed that 4 weeks of exposure of these animals to ambient particles induced a local inflammatory response in the lung, a systemic inflammatory response including stimulation of the marrow, and caused progression of atherosclerosis in both the aorta and coronary arteries (76, 77). Quantitative histologic studies showed an increase in plaque lipid content, a higher cell turnover in the plaques, and a thinner plaque cap (77). These morphologic changes are characteristic of plaque instability and vulnerability (78) and implicate lung inflammation as a potential risk factor for the development of atherosclerosis and its complications such as ischemic heart disease, stoke, and peripheral vascular disease.


   SUMMARY
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 ABSTRACT
 LUNG INFLAMMATION CAUSES A...
 SUMMARY
REFERENCES
 
Epidemiologic analyses have shown a relationship between COPD and an increase in mortality and morbidity from cardiovascular diseases. The possible biological mechanisms responsible for this association are numerous. Figure 4 shows hypothetical pathways for how lung inflammation could augment not only lung disease but also cause vascular and heart disease. We have shown that the alveolar macrophage and bronchial epithelial cells are important in secreting the mediators that elicit the local and a systemic inflammatory response when exposed to cigarette smoke or particulate matter air pollution. Stimulation of the bone marrow is an important component of the systemic response to lung inflammation. The cytokines produced in the lung are capable of stimulating the marrow to produce a leukocytosis, increase platelet counts, and stimulate the liver to produce acute phase proteins such as CRP and fibrinogen. These acute phase proteins may increase blood coagulability, which is a predictor of total cardiovascular morbidity and mortality in large population studies. We conclude that lung inflammation induced by inhalation of cigarette smoke and ambient particles induces a systemic inflammatory response. This in turn leads to endothelial activation and changes in atherosclerotic plaques typical of plaque instability. We speculate that these vascular changes contribute to the increase in cardiovascular morbidity and mortality associated with COPD.



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  		Figure 4. Proposed mechanisms of lung inflammation induced vascular disease. Inhaled cigarette smoke or ambient particles are processed by alveolar macrophages and lung epithelial cells. These cells produce proinflammatory mediators such as cytokines that promote a local inflammatory response in the lung that are thought to contribute to the exacerbation of chronic obstructive pulmonary disease and asthma and promote lung infection. These inflammatory mediators also translocate into the circulation and induce a systemic inflammatory response. This response includes stimulation of the marrow to release leukocytes and platelets, activation of the acute phase response with the production of procoagulation factors, and activation of endothelium. Together these effects could precipitate or aggravate underlying vascular disease with the development of acute cardiovascular events such as acute coronary thrombosis, arrhythmias, and heart failure.

 

   FOOTNOTES
 
This work was supported by the Heart and Stroke Foundation of BC & Yukon and National Institute of Health. S.F.v.E. is the recipient of a Career Investigators award from the American Lung Association and the William Thurlbeck Distinguished Researcher Award.

Conflict of Interest Statement: S.F.v.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.Q. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.C.H. served as a consultant to Altana Pharmaceuticals in 2003 and 2004 and received less than $5,000 in each of those years, served on the Canadian Advisory Board for GlaxoSmithKline (GSK) for 1 year (2003) and received $2,000 for that contribution, has participated as a speaker in scientific meetings and courses organized and financed by various pharmaceutical companies, including AstraZeneca and Altana Pharmaceuticals, annually receives funding from GSK as research grants, serves as the principal investigator on a jointly sponsored Canadian Institute of Health Research (CIHR) industry sponsored grant supported one-third by CIHR and two-thirds by industry, and this grant application was funded after peer review by the regular CIHR mechanism and the funds received from industry are directly related to the operating costs of the study.

(Received in original form June 9, 2004; accepted in final form August 20, 2004)


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