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The Proceedings of the American Thoracic Society 4:626-634 (2007)
© 2007 The American Thoracic Society
doi: 10.1513/pats.200706-071TH
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Systemic Inflammation in Chronic Obstructive Pulmonary Disease

The Role of Exacerbations

Emiel F. M. Wouters1, Karin H. Groenewegen1, Mieke A. Dentener1 and Juanita H. J. Vernooy1

1 Department of Respiratory Medicine, University Hospital Maastricht, Maastrict, The Netherlands

Correspondence and requests for reprints should be addressed to Prof.dr. E. F. M. Wouters, Department of Respiratory Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. E-mail: e.wouters{at}lung.azm.nl

ABSTRACT

The systemic manifestations of chronic obstructive pulmonary disease (COPD) exacerbations are recognized, but our understanding of their etiology and importance is lacking largely due to the small number of systematic and longitudinal studies. Most of the systemic manifestations are likely the result of inflammatory processes. Serum biomarkers, such as various cytokines, adipokines, C-reactive protein, and coagulation factors, are elevated during exacerbations. Our understanding of the systemic manifestations can be greatly enhanced if we integrate what is known about the basic science of systemic mediators with the translational science of their role in COPD exacerbations. Many overlapping connections and promising avenues of future research come to light with such a viewpoint.

Key Words: systemic inflammation • COPD, exacerbation • C-reactive protein

Chronic obstructive pulmonary disease (COPD) is a major worldwide disease and exacerbations of COPD are considered to be the key drivers of morbidity and mortality associated with this disease. In the past, the definition of COPD has been based on pulmonary pathophysiology—airflow limitation that is not fully reversible and usually progressive. Now it is widely recognized that this airflow limitation is associated with an abnormal inflammatory response (1) and that it is a multicomponent disease (2, 3) with extrapulmonary effects that contribute to disease severity (1). Thus, COPD can be considered a disease with organ-specific characteristics and systemic manifestations. Like other diseases that have an unclear etiology, there is a mosaic of processes that contribute to the pathogenesis of COPD, including variable gene expression, abnormal immune responses, the influence of hormones, and the damaging effects of factors in the environment (4). Because of the absence of an adequate conceptual framework and an advocacy that desires to lump different expressions of the disease together, many pieces of this complex mosaic remain unexplored. In most research on chronic inflammatory diseases, such as autoimmune disorders, environmental factors are viewed more as triggers that initiate the overt expression of an underlying disease process (4, 5). In COPD, research is largely focused on the effects of environmental factors, as both initiators and causative agents, with little attention given to underlying, or predisposing, conditions.

Despite the recognition of COPD as a multicomponent disease, exacerbations are defined only in terms of respiratory symptoms: worsening of dyspnea, cough, and/or sputum production that is acute in onset and may warrant a change in the regular medication regimen (1, 6). However, consistent with COPD being a systemic disease, disturbed sleeping as well as fatigue have been reported to be as important as dyspnea by patients hospitalized for an acute exacerbation of COPD (7).

The role of bacterial infections in exacerbations remains controversial, but at least 50% of patients have a high concentration of bacteria in their lower airways during an exacerbation (8–11). The link between bacterial infection and COPD exacerbations is further supported by the fact that immune responses that are bacterial strain specific are seen, and by the fact that bacterial exacerbations are associated with neutrophilic inflammation, as is COPD in general (12–15). Viral respiratory infections have also been associated with the severity and frequency of exacerbations (16).

SYSTEMIC EFFECTS OF EXACERBATIONS OF COPD

Although extrapulmonary effects are considered to contribute to the severity of COPD, the medical literature contains for the most part only cross-sectional studies that have evaluated clinical variables or enumerated cell types and/or concentrations of inflammatory mediators. Longitudinal studies investigating potential markers as prognostic indicators, or as discriminators between different disease stages, are limited. A recent meta-analysis showed that many clinical, cytologic, and biochemical variables in COPD have little or no correlation with FEV1-based disease staging. Only systemic concentrations of tumor necrosis factor (TNF)-{alpha} and C-reactive protein (CRP) showed a trend toward separation between disease stages (17).

Because it is well appreciated that there is enhancement of local airway inflammation during exacerbations (18, 19), more attention is also being given to the exacerbation-induced enhancement of systemic inflammation. Furthermore, finding a biomarker in blood that aids in diagnosis and defines outcomes of exacerbations would be a significant clinical advance, because, currently, diagnosis and outcome are based on symptoms and/or measures of health care utilization (1). This may prove to be difficult when one considers that reported symptoms and their interpretation are prone to interobserver variability, perhaps explaining why most variables and measures show weak relationships with the levels of exacerbation severity, with the exception of blood arterial carbon dioxide tension and breathing rate. Therefore, a more robust definition of exacerbation may be necessary before we can reliably identify objective markers of disease activity (20).

Various studies report that systemic inflammation is up-regulated during exacerbations. Markers reported to be higher in blood during exacerbation compared with the baseline include CRP (21–24), IL-8 (25), TNF-{alpha} (26), leptin (26, 27), endothelin-1 (28), eosinophil cationic protein, myeloperoxidase (29), fibrinogen, IL-6 (30), {alpha}1-antitrypsin (31), and leukotriene E4 (32) and leukotriene B4 (25) (Table 1). Moreover, serum IL-6 and CRP concentrations during exacerbations correlate with selected markers of airway inflammation, and seem to be higher in the presence of a bacterial pathogen (33). This correlation of systemic and airway inflammation has been shown to be lower airway specific (34), suggesting that it is not simply a result of pan-systemic inflammation.


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  		TABLE 1. SYSTEMIC MEDIATORS KNOWN TO BE ELEVATED DURING CHRONIC OBSTRUCTIVE PULMONARY DISEASE EXACERBATIONS

 
A recent study assessed the ability of 36 different biomarkers to confirm the presence of an exacerbation and predict its severity and found that CRP was the most selective (18). Besides CRP, only levels of IL-6, myeloid progenitor inhibitory factor (MPIF)-1, pulmonary and activation–regulated chemokine (PARC), adiponectin (ACRP-30), and soluble intercellular adhesion molecule (sICAM)-1 were found to significantly vary between baseline and exacerbation. The clinical implication of these changes for confirmation of exacerbation was limited because, at a cutoff value of 5 mg/L, CRP sensitivity was only 76% and specificity 57.5%. Elevated CRP concentrations during the recovery period of an exacerbation has been shown to be predictive of a failure to completely resolve symptoms and the recurrence of exacerbation (35). Furthermore, although CRP values are normal in nearly 50% of patients admitted for an exacerbation of COPD, they do relate to patient-reported presence of increased sputum purulence (36).

Copeptin, the more stable C-terminal part of the vasopressin precursor and a 39-amino-acid–long glucosylated peptide (37), has also been studied. Copeptin remains stable ex vivo for several days at room temperature in serum or plasma and directly reflects levels of vasopressin. In comparison to CRP, copeptin was superior in predicting the course of exacerbation; elevated copeptin levels at hospital admission predicted in-hospital outcome and length of hospital stay. Elevated copeptin levels also predicted long-term clinical failure, including survival, independent of lung function impairment, comorbidities, or hypoxemia.

The finding that the majority of tested biomarkers do not appear capable of improving clinical judgment can partially be related to the selection of the panel of biomarkers and the recognized heterogeneity of acute exacerbations. Using a proteomic approach, Pinto Plata and colleagues found that a panel of 24 serum biomarkers, selected from a microarray analysis of 143 biomarkers, correlated with the exacerbation rate for patients with COPD (38). This study demonstrates that consideration of a large number of biomarkers is important and that the relationship between systemic inflammation and COPD exacerbations is multidimensional.

ADAPTIVE AND INNATE IMMUNITY: LIKELY CAUSATIVE FACTORS OF SYSTEMIC MANIFESTATIONS OF COPD EXACERBATIONS

Despite the acknowledgment that adaptive immunity plays an important antimicrobial role in the respiratory mucosa, the adaptive immune responses during exacerbations of COPD have been poorly studied and the mechanisms behind the the host microorganism defense responses in COPD are poorly understood. Nonetheless, we know that inducible cell migration is triggered during respiratory infections as a result of the sensing of pathogens through pattern recognition receptors, Toll-like receptors (TLRs), thus augmenting the killing of invading pathogens (39). These events are mediated by two types of signals: diffusible chemotactic factors and cell surface adhesion molecules. Key inflammatory chemokines produced during acute microbial infection include IL-8, growth-related oncogene (GRO)-{alpha}, monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, MCP-4, macrophage inflammatory protein (MIP)-1{alpha}, MIP-1β, and RANTES (regulated upon activation, normal T-cell expressed and secreted) (40–42). These chemokines bind to the luminal surface of the vascular endothelium and trigger activation of the leucocytes, inducing conformational changes in the integrins (39, 40, 43, 44). These activated integrins on the leucocytes allow firm adhesion to the vascular endothelium. Integrin ligands on the endothelium, such as ICAM-1, are also induced either directly by TLRs expressed on the endothelium or indirectly through TNF-{alpha} and IL-1, which are induced by TLR-activated macrophages (40). In addition to the inflammation-induced cell recruitment, most tissues of the body are interlaced with resident innate leukocytes such as dendritic cells (DCs), macrophages, and mast cells. The role of DCs and the involvement of the CCL20-CCR6 receptor has been recently further elucidated in COPD. Particularly, the involvement of the CCL20-CCR6–DC axis in exacerbations of COPD is intriguing and urgently needs further evaluation (45, 46). CCL20 shares a high degree of structural homology with the β-defensins. In bronchoalveolar lavage from patients with cystic fibrosis, CCL20 is abundantly present and CCL20 displayed antimicrobial activity against mainly gram-negative bacteria and permeabilized bacterial membranes in a range intermediate to human β-defensins 2 and 3 (46). This multivariate adaptive immune response consisting of a host of cell types, cytokines, receptors, adhesion molecules, and biological factors effectively marshals systemic processes to combat local infections, and is thereby at least in part likely to be responsible for the systemic consequences of exacerbations of COPD.

COPD EXACERBATIONS: LESSONS TO BE GLEANED FROM CURRENT KNOWLEDGE OF SYSTEMIC MEDIATORS

To better understand the role of systemic involvement in COPD exacerbations, it is helpful to integrate some of the basic science of systemic mediators with the findings of more clinical and translational research across the disease spectrum. The basic, clinical, and translational science of CRP, adipose tissue, endothelial dysfunction, and hemostasis is discussed below in the context of these mediators' known and potential role in COPD exacerbations.

CRP: the Biological Role of the Acute-Phase Response
During the last decade, there has been compelling evidence that CRP is not just a marker of disease but also contributes to pathogenesis. Further expansion of our knowledge of the structure and function of CRP is crucial if we are to improve our understanding of the pathogenesis and heterogeneity of COPD.

CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae, is a sensitive marker of inflammation and tissue damage (47). The acute-phase response comprises the nonspecific physiologic and biochemical responses of endothermic animals to most forms of tissue damage, infection, inflammation, and malignant neoplasia. In particular, the synthesis of a number of proteins is rapidly up-regulated, principally in hepatocytes under the control of cytokines originating at the site of pathology. Other acute-phase proteins include proteinase inhibitors and coagulation proteins, complement, and transport proteins (47). Plasma CRP is produced mainly by hepatocytes, predominantly under transcriptional control by IL-6. The plasma half-life of CRP is about 19 hours and is constant under all conditions of health and disease, so that the sole determinant of circulating CRP concentration is the synthesis rate (48), which thus directly reflects the intensity of the pathologic process stimulating CRP production. Subjects in the general population have stable CRP concentrations that are characteristic for each individual. CRP belongs to the pentraxin family of calcium-dependent ligand-binding plasma proteins. The human CRP molecule is composed of five identical nonglycosylated polypeptide subunits, each containing 206 amino acid residues (49). Human CRP binds with the highest affinity to phosphocholine residues, but it also binds to a variety of other autologous and extrinsic ligands, and it aggregates or precipitates the cellular, particulate, or molecular structures bearing these ligands (50). Phosphocholine is a component of many prokaryocytes and is almost universally present in eukaryocytes (51). The capacity to bind these residues may be important for both host defense and handling of autologous constituents, including necrotic and apoptotic cells (50, 52–54). Autologous ligands include the native and modified plasma lipoproteins, damaged cell membranes, a number of different phospholipids and related compounds, small nuclear ribonucleoprotein particles, and apoptotic cells (50, 52, 55). Extrinsic ligands include many glycans, phospholipids, and other constituents of microorganisms, such as capsular and somatic components of bacteria, fungi, and parasites, as well as plant products (50). When aggregated or bound to macromolecular ligands, human CRP is recognized by C1q and potently activates the classical complement pathway (50, 56, 57). Indeed, C1q is a pattern recognition molecule that can trigger rapid enhanced phagocytosis, resulting in efficient containment of pathogens or clearance of cellular debris, apoptotic cells, and immune complexes. The complement system is a powerful effector mechanism, which, upon activation, generates activation fragments (C3a and C5a) responsible for the initiation of a local inflammatory response by recruitment of leukocytes to the area of infection or injury, and results in the assembly of the membrane attack complex (MAC or C5b-C9). C1q is a member of a family of proteins categorized as defense collagens. The globular carboxyl terminal portion of these proteins recognizes broad categories of molecules, including pathogen-associated molecular patterns (PAMPs), and the collagen-like N-terminal domain links the invading organism to complement-mediated or phagocyte effector mechanisms of the immune system. Membrane-bound defense collagens include the type A macrophage scavengers receptors, C1q, the collectins (mannose binding lectin, pulmonary surfactants A and D, conglutinin), and the more recently isolated members as the ficolin family and adiponectin (Acrp30, the adipocyte complement [C1q]–related protein of 30 kD) (58).

Few studies have reported that the complement system may participate in the inflammatory process of COPD (59, 60). One study evaluated C5a concentrations in the induced sputum of patients with COPD. Significantly elevated levels of C5a were found in the induced sputum of patients with COPD. C5a concentrations in patients with COPD correlated negatively with diffusing capacity (61).

In summary, CRP may actively participate in the pathogenesis of COPD through the complement system, an idea that is supported by evidence of complement system activation in COPD. Although it has not been reported in COPD, CRP has been found in the sputum from patients with inflamed airways, which means it has the potential to participate in airway inflammation (62). From an integrative viewpoint, therapeutic targeting of CRP could focus on any of the above listed facets of the CRP axis.

Fat Tissue during Exacerbations: a Leptin/Adiponectin Imbalance?
Until recently, fat was considered to function predominantly as the triglyceride reservoir of the body and was believed to have only a passive endocrine role. It is now recognized that white adipose tissue is a multifunctional organ. White adipose tissue secretes several hormones and a diverse range of protein factors that have been given the collective name "adipocytokines" or "adipokines" (63). Adipocytes themselves have been found to secrete proteins involved in lipid metabolism, insulin sensitivity, the alternative complement system, vascular homeostasis, blood pressure regulation and angiogenesis, as well as the regulation of energy balance (64). Of particular interest, leptin and adiponectin have been linked to acute exacerbations and stable COPD (26, 65). The complex interrelationship among leptin and adiponectin, inflammatory processes, and immune responses is discussed below, with an eye toward implications for the future.

Leptin.
Leptin is a peptide hormone that is produced predominantly by white adipose cells (66, 67). The mature protein is a 16-kD nonglycosylated protein that belongs to the type I cytokine superfamily. Circulating leptin is proportional to the amount of adipose tissue in any given individual. Leptin exerts most of its energy metabolism effects through effects on the central nervous system, namely the hypothalamic nuclei. These effects include decreases in food intake, increases in energy expenditure, and decreases in metabolic efficiency. In addition, leptin has been shown to influence a wide spectrum of biological functions, including lipid and glucose metabolism, synthesis of glucocorticoids and insulin, regulation of the hypothalamic–pituitary–adrenal axis, maturation of the reproductive system, hematopoiesis, angiogenesis, and fetal development (68–76). It is therefore not surprising that, during acute exacerbations, leptin concentrations have been shown to relate to disturbances in the energy balance and the systemic inflammatory response (27).

The leptin receptor (Ob-R) is encoded by the diabetes (db) gene (77, 78). Ob-R has at least six isoforms, a result of alternative splicing, that all share an identical extracellular ligand-binding domain but have cytoplasmic domains of varying lengths (79). The full-length functional isoform Ob-Rb contains intracellular motifs required for activation of the Janus-activated kinase as well as signal transduction and activation of the transcription pathway JAK/STAT (79). Furthermore, the almost universal distribution of leptin receptors reflects the multitude of leptin's biological effects outside the central nervous system.

Recently published studies demonstrate that leptin has a potentiating role in the function of both innate and adaptive immunity (80). Leptin stimulates neutrophils and macrophage chemotaxis (81), and enhances their functional capacities such as oxidative burst (81), phagocytosis (82), and cytokine secretion (83, 84). In addition, leptin exerts activating (85) and proliferating (86) effects on T lymphocytes and promotes Th1 cell differentiation (87). Furthermore, leptin enhances host responses to inflammation and infection by stimulating tissue repair via its mitogenic and angiogenic effects on epithelium and endothelium (72, 88).

All of the above has led to the general consensus that leptin has a proinflammatory role in the regulation of inflammation and immunity. In patients with rheumatoid arthritis, it has been shown that fasting results in an improvement of clinical and biological measures of disease activity, and that this improvement correlates with a marked decrease in serum leptin concentration as well as a shift toward a Th2 cytokine profile (89). Interestingly, in chronic autoimmune disorders such as multiple sclerosis, circulating leptin concentrations correlate significantly with the percentage of circulating CD4+CD25+ regulatory T cells (Tregs) (90). Tregs are known to dampen autoimmune responses mediated by CD4+CD25– T cells and may thereby delay the onset and dampen progression of autoimmune disorders (91). Such findings may well have implications for improving our understanding of the pathogenesis of autoimmunity and are likely to improve future therapy for autoimmune disorders. More research is needed to better our understanding of the role of elevated concentrations of leptin during exacerbations of COPD, particularly regarding the role of leptin in local respiratory defense (92, 93).

In summary, leptin does function as a proinflammatory cytokine and is involved in the pathogenesis of inflammatory and autoimmune diseases, including acute exacerbations of COPD.

Adiponectin.
Adiponectin is the adipokine that is best known for its role in the regulation of insulin sensitivity and is found in the circulation at the highest concentration of any adipokine (in the microgram per millimeter range vs. nanograms per millimiter for leptin) (94). The adiponectin molecule is composed of a globular and a collagenous domain and is present in the circulation as trimers and oligomers (95). The globular domain of adiponectin presents close structural similarities with TNF-{alpha} (96). Leukocyte elastase cleaves adiponectin and generates the globular domain, which can trimerize but does not further polymerize (96, 97), indicating that activated leukocytes might modulate adiponectin bioactivity. Serum adiponectin levels do not increase with obesity. Adiponectin has important antiinflammatory effects. Adiponectin reduces the production and activity of TNF-{alpha} and inhibits IL-6 production, and this antiinflammatory activity is accompanied by induction of the antiinflammatory cytokines IL-10 and IL-1 receptor antagonist (98–101). Inhibition of the nuclear factor (NF)-{kappa}B by adiponectin might explain these effects (101). Interestingly, increased concentrations of soluble IL-1 receptor during recovery of acute exacerbations have been reported (23). In addition, adiponectin reduces induction of the endothelial adhesion molecules ICAM-1 and vascular cell adhesion molecule 1 (102, 103). On the basis of all of the above-mentioned effects, it appears that adiponectin acts as an antiinflammatory molecule.

In total, the above-reported data strongly implicate both leptin and adiponectin in the inflammatory process that is part of the pathogenesis of exacerbations of COPD.

Thus, we can think of adipose tissue as an important contributor to the systemic manifestations of COPD, and particularly COPD exacerbations. Indeed, the inflammatory/antiinflammatory effects of adipokines highlight the fact that adipose tissue is more than an energy storage organ, and they also highlight the importance of body composition in the pathogenesis of COPD. This latter point is of particular interest when one considers that obesity, even in the absence of other inflammatory conditions including COPD, is associated with a low-grade chronic inflammatory state. Is body composition thereby a predisposing factor for the development of COPD and/or exacerbations? This area of research is in need of a more longitudinal and systematic approach to these questions. In addition, focus should not be placed on a singular adipokine, because the opposing effects of leptin and adiponectin suggest that adipokine ratios may be of greater interest.

Endothelial Dysfunction during Exacerbations of COPD
Endothelial dysfunction can be viewed as an imbalance between vaso-relaxing and vaso-constrictive substances produced by endothelial cells (104). The up-regulation of the expression of adhesion molecules in the vascular endothelium is considered to be the initiating event in atherogenesis. A number of the biochemical markers that are associated with COPD are also associated with endothelial dysfunction: CRP, sICAM-1, IL-6, TNF-{alpha}, endothelin-1, complement, and leptin. In particular, CRP, fibrinogen, and complement are discussed below.

CRP is one of the strongest independent predictors of vascular death in various settings (105–107). Furthermore, although CRP was initially studied as a noncontributing biomarker, it is now understood to be involved in atherogenesis (108). CRP potently down-regulates endothelial nitric oxide synthase (eNOS) transcription and destabilizes eNOS mRNA, which decreases both basal and stimulated NO release (109). CRP has been shown to stimulate endothelin-1 and IL-6 release, to up-regulate adhesion molecules, and to stimulate MCP-1 while facilitating macrophage low-density lipoprotein uptake (110). CRP has been shown to facilitate endothelial cell apoptosis, to inhibit angiogenesis, and to up-regulate NF-{kappa}B (111). The proatherogenic effects of CRP extend beyond the endothelium to the vascular smooth muscle, where it directly up-regulates angiotensin type 1 receptors and stimulates vascular smooth muscle migration, proliferation, neointimal formation, and reactive oxygen species production (112). CRP directly inhibits endothelial progenitor cell differentiation, survival, and function. This ability of CRP to inhibit endothelial progenitor cell differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease (113). Plasma fibrinogen levels are also elevated during acute exacerbations and can further predispose patients with COPD to develop cardiovascular events.

Leptin exerts many potentially atherogenic effects, such as the following: induction of endothelial dysfunction; stimulation of inflammatory reactions; oxidative stress; decrease in paraoxonase activity; playing an important role in oxidative modification of plasma lipoproteins, platelet aggregation, migration, and hypertrophy; and proliferation of vascular smooth muscle cells (114).

An intriguing process is the cross-talk between the complement system and the endothelial cells as recently reviewed by Fischetti and Tedesco (115). Endothelial cells secrete several complement components that contribute to the circulating pool. This process is regulated by cytokines and is affected by proinflammatory stimuli, such as hypoxia and tissue reoxygenation. Stimulation by complement activation products causes endothelial cells to adopt a proinflammatory and coagulation promoting state. Expression of regulatory molecules on the cell surface provides protection against this undesired attack by complement activation products. This unrestricted complement activation may lead to structural and functional changes of the endothelium (115).

In summary, the potential exists for COPD exacerbations to initiate or promote endothelial dysfunction. It is therefore important that future studies evaluate endothelial dysfunction and vascular changes during exacerbations of COPD.

Systemic Inflammation and Hemostasis
A prothrombotic condition has been documented by various studies in patients with COPD. An increased rate of platelet aggregation has been found in patients with hypercapnia and/or hypoxemia (116, 117), and a number of studies have demonstrated increased platelet activation in patients with COPD (118–120). Markers of hypercoagulation, thrombin–antithrombin III complex (TAT), fibrinopeptide A, and plasminogen activator inhibitor type 1 (PAI-1), have been shown to be significantly higher in patients with COPD than in healthy control subjects (121). The role of smoking in coagulation and thromboembolism in COPD has been recently extensively reviewed (122).

Blood coagulation is part of an important host defense mechanism termed "hemostasis." Thrombosis is a pathologic process in which a platelet aggregate and/or fibrin clot forms in the lumen of an intact blood vessel or in the chamber of the heart. Coagulation in vivo is the result of activation of the intrinsic or extrinsic pathways of the coagulation cascade. This involves coagulation protease zymogens, fibrinogen and thrombin, which are secreted by hepatocytes into the bloodstream. Fibrinogen consists of three pairs of polypeptide chains covalently linked by disulfide bonds. Thrombin (IIa) converts fibrinogen to fibrin monomers by cleaving fibrinopeptides A and B from the N-terminal ends of the A{alpha} and Bβ chains. Removal of the fibrinopeptides allow the fibrin monomers to form a gel of long polymers. The formation of stable, fibrinolysis-resistant, cross-linked fibrin is the ultimate step in coagulation and occurs as a result of concurrent activation of factor XIII and the generation of crosslinked fibrin polymers (123, 124). The main fibrinolytic components of plasma are plasminogen, {alpha}2-antiplasmin, tissue plasminogen activator (t-PA), and urinary-type plasminogen activator. The two principal inhibitors of fibrinolysis in the circulation are PAI-1 and {alpha}2-antiplasmin, a specific plasmin inhibitor that is covalently bound to polymerizing fibrin by activated factor XIII (125).

Inflammatory mechanisms shift the hemostatic balance toward a balance that favors the activation of coagulation (126). Inflammation can increase fibrinogen concentrations and such an increase has been reported in patients with stable and exacerbating COPD (30, 127). Probably the best-known contribution of inflammation is the induction of tissue factor expression on the cell surface of leukocytes, particularly monocytes (128, 129). Inflammation also increases CRP. CRP has been shown to facilitate monocyte–endothelial cell interactions and to promote PAI-1 and tissue factor (130–132). CRP can contribute to complement activation, as outlined above, and the complement system activates the coagulation system in multiple ways (115). Inflammatory mediators, such as IL-6, increase platelet production (133). Platelet responsiveness can also be increased indirectly by inflammatory mediators and can induce expression of protease activated receptors on the endothelium (134). In inflammatory conditions, antithrombin inhibitory activity is decreased and this results in delayed inhibition of the coagulation enzymes that favor intravascular coagulation (135). In addition to decreasing antithrombin concentrations, the concentration of vascular heparin-like molecules can be reduced by inflammatory cytokines and neutrophil activation products (136). Of the natural anticoagulant pathways, the protein C pathway appears to be especially sensitive to down-regulation by inflammatory mediators. Endotoxin, IL-1β, and TNF-{alpha} all down-regulate both thrombomodulin and endothelial cell protein C receptor (137, 138).

Once control of thrombin and other coagulation enzymes is lost, they can participate in promoting the inflammatory response (126). Platelets contain, and are capable of releasing, high concentrations of the proinflammatory mediator CD40 ligand. This cytokine induces tissue factor synthesis and increases inflammatory cytokines, such as IL-6 and IL-8 (139–142). In this way, inflammatory mediators leading to increased platelet number and responsiveness set in motion the ability to generate additional inflammatory responses (126). Thrombin is involved in many cellular and humoral responses of inflammation and cell proliferation (126). Tissue factor–factor VIIa complex can activate protease activated receptors, leading to increased expression of adhesion molecules that facilitate leukocyte-mediated vessel injury (143, 144). Finally, fibrin can participate in regulation of different aspects of inflammation (145).

CONCLUSIONS

Exacerbations are important events in the natural history of COPD and an active field of research. However, the current research paradigm largely underestimates the importance of factors that orchestrate host responses and undervalues the interplay between the innate and adaptive immunity. Furthermore, there is more need to examine the role of systemic inflammation, as it is at the very least involved with the alterations of physical conditions observed during COPD exacerbations. In addition, a wide variety of systemic effects are seen during exacerbations: acute-phase protein elevation, triggering of the complement system, changes in adipokine concentrations, endothelial dysfunction, and a shift of the hemostatic balance to promote coagulation (Figure 1). Broadening our viewpoint beyond respiratory symptoms and considering systemic factors will undoubtedly improve our understanding of the process of COPD exacerbations. In so doing, we will also improve disease management and facilitate the identification of new therapeutic targets, ultimately leading to a reduction in morbidity and mortality related to exacerbations of COPD.


Figure 1
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  		Figure 1. Venn diagram illustrating the connections between systemic mediators, systemic manifestations, immune response, infection, and the clinical syndrome of chronic obstructive pulmonary disease exacerbation. Gray shading indicates an antiinflammatory effect. CRP = C-reactive protein; PAI/TF = plasminogen activator inhibitor/tissue factor; wt = weight.

 
ACKNOWLEDGMENTS

The authors thank Dr. Scott Wagers for critical review of this manuscript.

FOOTNOTES

Conflict of Interest Statement: E.F.M.W. is a member of the scientific advisory boards for GlaxoSmithKline (GSK), Boehringer Ingelheim, AstraZeneca, and Numico. He received lecture fees from GSK, AstraZeneca, and Boehringer Ingelheim. He received research grants between 2004 and 2006 from GSK, AstraZeneca, Boehringer Ingelheim, Centocor, and Numico. K.H.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.A.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.H.J.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form June 15, 2007; accepted in final form August 27, 2007)

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