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The Proceedings of the American Thoracic Society 2:26-33 (2005)
© 2005 The American Thoracic Society

Local and Systemic Inflammation in Chronic Obstructive Pulmonary Disease

Emiel F. M. Wouters

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

Correspondence and requests for reprints should be addressed to Emiel F. M. Wouters, M.D., Ph.D., Department of Pulmonary Diseases, University Hospital Maastricht, P.O. Box 5800, 6202 As Maastricht, The Netherlands. E-mail: ewo{at}ms-azm-3.azm.nl


   ABSTRACT
TOP
 ABSTRACT
PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
 REFERENCES
 
There is growing evidence for systemic inflammation in chronic obstructive pulmonary disease (COPD). Increased circulating levels of inflammatory cytokines and acute phase proteins occur in stable disease, and COPD exacerbations are notably associated with pulmonary and systemic inflammation. Although the course of inflammation is determined by the balance between pro- and antiinflammatory mediators, in COPD most attention has focused on the former. During exacerbation, however, upregulation of antiinflammatory markers occurs. The main causes of systemic inflammation in COPD remain to be elucidated, although systemic hypoxia is a candidate factor. Although a relationship between lung and systemic inflammation has been suggested, experimental evidence indicates no direct correlations in the regulation of inflammation in the pulmonary and systemic compartments. Longitudinal studies are needed to unravel the role of systemic inflammation in the course of COPD, to analyze the role of acute exacerbations on the chronicity of inflammation, and to evaluate the response of systemic inflammation to different interventions. Emphasis should be placed on the identification of signaling pathways induced and/or altered in skeletal muscle by inflammation, as muscle wasting is a prominent feature of chronic inflammatory disease conditions and contributes significantly to impaired physical functioning and health status in COPD.

Key Words: chronic obstructive pulmonary disease • cytokines • immune response • systemic inflammation

Chronic obstructive pulmonary disease (COPD) is defined as a disease state characterized by poorly reversible airflow limitation that is usually progressive and associated with an abnormal inflammatory response of the lung (1, 2). Cigarette smoking is the most important risk factor and, at present, cessation of smoking is the only intervention that can bring about significant attenuation of the lung function impairment (1, 2).The pathologic hallmarks of COPD are inflammation of the peripheral airways and destruction of the lung parenchyma contributing to the functional consequence of expiratory airflow limitation. To unravel the pathogenic mechanisms which may contribute to the impaired health status of patients suffering from COPD, there is growing consensus to approach COPD as a multi-component disease with manifested systemic abnormalities.


   PULMONARY INFLAMMATION IN COPD
TOP
 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
 REFERENCES
 
Pulmonary Cellular Changes in COPD
The development of airflow limitation in COPD is associated with cellular and structural changes in both peripheral and central airways, while the inflammatory process extends to the lung parenchyma and pulmonary arteries. Indeed, it is now accepted that cigarette smoking can elicit an inflammatory reaction involving the entire tracheobronchial tree even in the absence of an established airflow limitation (3, 4). Studies examining central airways of smokers have shown that T lymphocytes and macrophages are the predominant cells infiltrating the airway wall, whereas neutrophils, which are scarce in the airway wall, are increased in the airway lumen (3, 5). Early lesions in the peripheral airways are an inflammatory cell infiltrate in the wall consisting predominantly of mononuclear cells and clusters of macrophages in the respiratory bronchioles (4). In smokers with established COPD, the development of airflow limitation is associated with a further increase of macrophages and T lymphocytes in the airway wall and of neutrophils in the lumen (5–7). In addition, there is a shift in the balance of the CD4+/CD8+ T lymphocyte ratio in favor of the CD8+ (7, 8). CD8+ cytotoxic T lymphocytes infiltrate the central and peripheral airways, the lung parenchyma, and the adventitial layer of the pulmonary arteries (7–10). The significant correlation between the number of CD8+ cytotoxic T lymphocytes and the degree of airflow limitation in COPD suggests a role of these cells in the progression of this disorder (7–10). Neutrophils are also increased in the bronchial glands of patients with COPD, indicating a crucial role in the development of mucus hypersecretion in COPD (11). It has also been reported that there is markedly increased interleukin (IL)-4 gene expression by relatively large numbers of inflammatory cells infiltrating the bronchial subepithelium and submucosal mucus-secreting glands of smokers with chronic bronchitis (12).

The microlocalization of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD further supports a role of these cell types in the pathogenesis of smoking-induced airflow limitation (13). A major characteristic of airflow limitation in COPD is its progressively worsening nature. In smokers, an association was found between the accelerated decline in lung function and the increased number of neutrophils in the airway lumen (14). In subjects with a more rapid decline in FEV1, neutrophils exhibited increased expression of CD11b/CD18, an important adhesion molecule whose ligand is intercellular adhesion molecule (ICAM)-1 (15). Macrophage phenotyping by immunohistochemistry with monoclonal antibodies directed against CD11b, CD14, E54, and CD71 revealed no significant differences between active smokers and ex-smokers with manifested COPD (16). Amplification of inflammation in patients with emphysema seems associated with latent adenoviral infection (17).

Disordered Cytokine and Chemokine Homeostasis in COPD
Advances in molecular techniques have yielded insights into cytokine-regulated control of inflammatory processes in recent years. Indeed, a complex cytokine network is involved in host defense and inflammation to ensure the activation and expansion of cells during an immune response and the controlled deletion of lymphoid cells that are no longer needed (18, 19). These mechanisms are integrated by extracellular cytokine receptors acting through signaling cascades that direct and coordinate intracellular responses. Most cytokines exert their function in a complex network where one cytokine can influence production of, and respond to, other cytokines. Although cytokines are fundamental to the inflammatory process in response to injury or infection, the disruption of their homeostasis can lead to local or systemic pathology as demonstrated in a variety of chronic inflammatory conditions (18, 19). Present knowledge of the pathogenesis of COPD is limited in comparison with other chronic inflammatory diseases such as rheumatoid arthritis (18, 19).

Tumor necrosis factor (TNF)-{alpha} is a potent proinflammatory cytokine known to exert its activities by interaction with two structurally related but functionally distinct transmembrane receptors, TNF-R55 and TNF-R75 (20). TNF-{alpha} coordinates the inflammatory process at the multicellular level by stimulating increased expression of adhesion molecules on leukocytes and endothelial cells, with upregulation of other proinflammatory cytokines, e.g., IL-1 and IL-6, and inducing angiogenesis. A rise in TNF-{alpha} levels in induced sputum of patients with severe COPD has been reported (5). Patients with COPD have significantly higher levels of soluble (s) TNF-R55 in sputum as compared with control subjects, and the sputum sTNFR levels were related inversely to FEV1 in patients with COPD (21). These soluble receptors for TNF-{alpha} are considered to be markers of a proinflammatory state because of their shedding from the cell membrane in response to endogenous TNF-{alpha} and other inflammatory mediators. Higher TNF-{alpha} levels in spontaneously expectorated sputum is also reported in patients colonized with Hemophilus influenzae in comparison with noncolonized but otherwise similar patients (22). No data are available presently regarding any possible diminution in production of other proinflammatory cytokines and attenuation of the inflammatory process by blocking of TNF-{alpha} in COPD. An increased expression of growth factors as vascular endothelial growth factor has been reported in pulmonary muscular arteries of patients with moderate COPD and in smokers with normal lung function as compared with nonsmokers (23).

Increased levels of IL-6 are found in exhaled breath condensate of patients with COPD (24) and stimulated primary cultures of human bronchial epithelial cells produced significantly more IL-6 than unstimulated cells from patients with COPD (25). Upregulation of cellular adhesion molecules on endothelial and epithelial cells has also been reported in COPD (26).

Generally, inflammation is characterized not only by upregulation of proinflammatory cytokines but also of the antiinflammatory cytokines and various cytokine inhibitors, including their soluble receptors. These inhibitory cytokines include IL-10, transforming growth factor (TGF)-ß (27), IL-11, and IL-1 receptor antagonist (IL-1Ra), which are released to limit the duration and extent of inflammatory responses. Limited data of the role of these antiinflammatory proteins in COPD is as yet available. One study reported significantly lower levels of IL-10 and of IL-10–positive cells in the sputum of patients with COPD (28). IL-10 is particularly interesting as an inhibitor of several inflammatory processes.

TGF-ß1 is a multifunctional growth factor that modulates cellular proliferation and induces differentiation and synthesis of extracellular matrix proteins, including collagens and fibronectin, in many types of cells. TGF-ß1 also induces chemotaxis of inflammatory cells such as mononuclear phagocytes, mast cells, and T lymphocytes (29–32). By studying pulmonary protein and mRNA distribution patterns of TGF-ß1, and protein expression levels of types I and II TGF-ß receptors, it was reported that in subjects with COPD higher expression of TGF-ß1 mRNA and protein were found in airway and alveolar epithelial cells as compared with subjects without COPD. A markedly higher expression of both TGF-ß receptors was found in macrophages of subjects with COPD (31–33). Furthermore, the higher expression of TGF-ß1 in bronchiolar epithelial cells correlated both with the increased numbers of macrophages and mast cells in the bronchiolar epithelium in COPD and with FEV1 values in current ex-smokers. Based on these observations, it was concluded that TGF-ß1 is implicated in the recruitment of macrophages and mast cells into the airway epithelium in COPD (33).

In the small airway epithelium from smokers and patients with COPD, it was reported that the levels of TGF-ß1 mRNA were significantly higher in smokers and patients with COPD compared with nonsmokers, and the magnitude of the TGF-ß1 signals showed a positive correlation with the burden of cigarette smoking. The level of TGF-ß1 gene expression correlates with the degree of peripheral airway obstruction, and cultured airway epithelial cells from smokers with and without COPD also release increased total TGF-ß1 protein compared with nonsmokers (34).

Based on the increased numbers of neutrophils in sputum of patients with COPD and the transient nature of these cells, neutrophil migration into the airways has been an area of much study. There are several reports indicating that endogenous production of IL-8, a CXC chemokine, plays a substantial role in mediating neutrophil recruitment and activation, and enhancing the subsequent inflammatory response. IL-8 is detectable in bronchoalveolar fluid from current smokers (35) and increased levels are reported in induced sputum of patients with COPD (21, 36, 37). Sputum levels of IL-8 correlate strongly with the degree of airflow limitation in patients with COPD (38). The importance of IL-8 in COPD is suggested by the observations that its specific inhibition of with an anti–IL-8 antibody led to a concentration-dependent reduction of sputum-induced neutrophil chemotaxis (38). In the same study, the contributing role of leukotriene B4 to neutrophil chemotaxis was evidenced by a concentration-dependent inhibition of neutrophil chemotaxis by addition of a selective leukotriene B4 receptor antagonist (38).

Growth-related oncogene (GRO)-{alpha} is another CXC chemokine, produced by a variety of cells including monocytes, endothelial cells, fibroblasts, and synovial cells. It can be induced by TNF-{alpha} in human bronchial epithelial cells and by lipopolysaccharide in alveolar macrophages (39). GRO-{alpha} is related structurally to IL-8 and is a powerful activator of neutrophils, demonstrating chemotactic activity for neutrophils as well as T lymphocytes and basophils (40, 41). Elevated GRO-{alpha} in induced sputum of patients with COPD has been reported, and was correlated negatively with the degree of airflow limitation (42). Significantly higher levels of monocyte chemoattractant protein (MCP)-1, a CC chemokine produced by monocytes, T lymphocytes, fibroblasts, endothelial cells, smooth muscle cells, and keratinocytes, were also found in induced sputum (37). MCP-1, via activation of CCR2 receptors expressed on monocytes and T lymphocytes, is a potent chemoattractant (37).

The role of chemokines in the pathogenesis of COPD is stressed by the observation of markedly increased expression of the CXCR3 and its ligand, CXCL10, in peripheral airways epithelium of smokers with COPD (43). That smokers with COPD have increased numbers of CXCR3+ cells in peripheral airways and that these cells are CD8+ and produce interferon (IFN)-{gamma} suggests a predominant role of CD8+ cells in the pathogenesis of COPD, and indicates that the CXCR3/CXCL10 axis may be involved in the recruitment of Th1 T cells in peripheral airways. These cells, through the production of IFN-{gamma} may further upregulate CXCL10 production, and the CXCR3/CXCL10 axis may be a mechanism for the amplification and maintenance of a T1-dominated inflammatory response in the lung (43).

Recent data have focused attention on the participation of the airway smooth muscle in the pulmonary inflammatory response in patients with COPD. Thus, airway smooth muscle cells also serve as a source of CXCL10 in inflamed airways. IFN-{gamma} and TNF-{alpha}, acting via transcription factor nuclear factor (NF)-{kappa}B, induce CXCL10 secretion, and both cytokines have a synergistic effect on CXCL10 expression in airway smooth muscle (44). These and other data demonstrate the active involvement of airway smooth muscle cells in the inflammatory process of COPD. Human airway smooth muscle cells release a variety of pro- and antiinflammatory mediators such as the chemokine IL-8 and granulocyte colony-stimulating factor (G-CSF), an important survival and activation factor for neutrophils (45–47).

Interestingly, neutrophils, the predominant cell in the airway lumen of patients with COPD, produce, among other chemokines, the three ligands for CXCR3: XCL10, CXCL9, and the IFN-{gamma}–inducible T cell chemoattractant, CXCL11 (48, 49). These data clearly indicate an involvement of the CXC and CC chemokines in the inflammatory processes associated with COPD. Interestingly, cytokines of the CXC family have a pivotal role not only in the control of inflammation but also of angiogenesis, as a result of the shared expression of their specific receptors by leukocytes and endothelial cells (50).


   SYSTEMIC INFLAMMATION IN COPD
TOP
 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
 REFERENCES
 
Circulating Inflammatory Cells
Many studies of COPD have reported changes in various inflammatory cells, including neutrophils and lymphocytes, in peripheral blood. The activation of peripheral blood neutrophils, resulting in potentiation of cytotoxic and migratory responses, has also been shown. Noguera and colleagues investigated the production of reactive oxygen species and the expression of surface adhesion molecules in circulating neutrophils of patients with COPD who were in a clinical stable condition (51, 52). Compared with control subjects, patients with stable disease showed an increased expression of CD11b/CD18 in circulating neutrophils with lower expression levels of ICAM-1. Increased plasma soluble ICAM-1, a surrogate of its expression on the endothelium, was reported by others (26). In addition, Noguera and coworkers showed that blood neutrophils isolated from patients with COPD produced more reactive oxygen species under basal conditions as well as after stimulation in vitro, as compared to neutrophils from smoking and nonsmoking control subjects, and this respiratory burst correlated with the elevated expression of adhesion molecules (52). In another study, Burnett and colleagues demonstrated that peripheral neutrophils isolated from patients with COPD showed enhanced chemotaxis and extracellular proteolysis in vitro (53, 54). In contrast, Cataldo and coworkers found no differences in the secretion of matrix metalloproteinase (MMP)-9 by circulating granulocytes comparing patients with COPD and control subjects (55). The expression of stimulatory Ga, a G protein subunit that is a key signaling protein for cell adhesion and activation in circulating neutrophils, has been shown to be downregulated irrespective of the clinical condition of the patient (51). However, the pathogenic implications of most of these findings are still unclear, and need confirmation in well characterized patient groups and in different phases of the disease process.

Although blood lymphocytes isolated from patients with COPD have been less well studied, recent findings indicate abnormal lymphocyte function in COPD. Increased activity of cytochrome oxidase, the terminal enzyme of the mitochondrial respiratory chain, was reported in the lymphocytes of patients with COPD compared with healthy subjects (56), and found to be significantly related to disease severity as reflected by the degree of airflow limitation. In a recent study, Hageman and colleagues (57) investigated activation of nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which forms extensive poly(ADP-ribose) polymers from its substrate NAD+ after activation by reactive oxygen species–induced DNA strand breaks. Activation of PARP-1 in peripheral blood lymphocytes of patients with COPD was more prevalent than in lymphocytes of healthy, age-matched control subjects, supporting a contribution of PARP-1 activation to the pathophysiology of COPD. PARP-1 activation was associated with a reduction of the NAD+ status, the consequences of which can include impaired production of high-energy phosphates (58).

In contrast to numerous studies showing a decreased pulmonary CD4+/CD8+ ratio in COPD, this has not to date been studied as extensively in the systemic compartment. Several reports suggest that cigarette smoke alone may trigger a shift in the numbers of CD4+ and CD8+ lymphocytes, which may be reversible after smoking cessation (59–62). In this respect, de Jong and coworkers (63) reported no significant differences between lymphocyte subsets in peripheral blood of patients with COPD and healthy smokers. However, these authors also found that, within the group of nonsmokers, the percentage of CD8+ cells was significantly higher in subjects with COPD compared with control subjects, and the CD4:CD8 ratio correlated positively with higher FEV1 values. Additional studies are necessary to understand better the contribution of circulating lymphocytes to the pathogenesis of COPD.

The propensity of circulating monocytes to release proinflammatory molecules as a possible factor in a systemic inflammatory response was evaluated recently in stable COPD. Monocytes isolated from patients with COPD release significantly more MMP-9 but less IL-8 than control subjects (64). Cell stimulation resulted in a larger enhancement of IL-6 and MCP-1 release from COPD monocytes, whereas monocytes from healthy individuals released higher levels of ICAM-1. Monocytes isolated from patients with COPD also showed a consistent but not statistically significant NF-{kappa}B activation, suggesting that this transcription factor might be involved in the activation of circulating monocytes in patients with COPD (64).

As a consequence of cellular inflammatory changes, different authors have reported changes in the oxidant/antioxidant balance in the systemic circulation. Markedly reduced Trolox-equivalent antioxidant capacity (TEAC) of plasma, as well as increased levels of lipid peroxidation products, both indices of overall oxidative stress, are seen in healthy smokers and patients with COPD versus nonsmoking control subjects (65, 66). However, no relationship was found between spirometric endpoints (FEV1 or FEV1/FVC) and the plasma levels of TEAC in patients with COPD, healthy smokers, or healthy nonsmokers. These findings have been confirmed and extended by Hageman and coworkers, who demonstrated a significant reduction of TEAC of deproteinized plasma as well as a reduction of plasma uric acid in patients with stable COPD when compared with control subjects (57). Further evidence of persistent systemic oxidative stress in patients with COPD was provided by the finding of higher levels of isoprostane F2{alpha}-II, a stable prostaglandin isomer formed by reactive oxygen species-dependent peroxidation of arachidonic acid, in the urine of patients with COPD versus smoking control subjects (67). Together these studies indicate that both smoking and COPD are associated with significant systemic oxidative stress.

Inflammatory Mediators in Plasma
During the last decade, several studies investigating systemic manifestations of COPD have reported enhanced levels of circulating inflammatory mediators, such as acute-phase reactants and cytokines. The acute-phase proteins are liver-derived, key players in innate immunity and reduction of inflammatory reactions. Schols and colleagues demonstrated increased levels of C-reactive protein and lipopolysaccharide binding protein in patients with stable COPD (68), and which was most pronounced in a subset of patients with COPD with an increased resting energy expenditure and decreased fat-free mass. The lack of a response to some intervention strategies such as nutritional therapy seems to be related to the level of this systemic inflammatory response (69). A prospective epidemiological study in a cohort of 8,955 subjects from a Danish general adult population study revealed that increased plasma levels of fibrinogen, another acute-phase reactant, are associated with reduced lung function and increased risk of COPD, independent of smoking status (70). The rise in the systemic levels of acute-phase proteins suggests that hepatocytes are activated to produce these reactants, although increasing evidence indicates that other tissue-specific cells such as lung epithelial cells, are also able to produce acute-phase proteins (71). The formation of acute-phase reactants is induced strongly by cytokines such as IL-6 or TNF-{alpha}. Indeed, enhanced circulating levels IL-6 and TNF-{alpha} have been reported in COPD (57, 72–75). The detection of biological active TNF-{alpha} can be hampered by its short half-life (~ 6–7 minutes), the formation of complexes with both sTNF-R subtypes, and its renal clearance. Small but significant increases in circulating levels of both sTNF-R55 and sTNF-R75 have also been demonstrated in COPD (21, 68, 76–78). Because inflammatory stimuli such as TNF-{alpha} will induce shedding of membrane-bound TNF-R75, the enhanced levels of sTNF-R may reflect the enhanced inflammatory status of patients with COPD. These increased levels of proinflammatory mediators are not counterbalanced by upregulation of antiinflammatory mediators like soluble IL-1RII in patients with stable COPD (76). Yasuda and colleagues investigated the association between apoptosis-related factors and the progression of COPD (74), and demonstrated that plasma levels of soluble Fas (CD95), an inhibitor of apoptosis, were increased significantly in severe COPD when compared to healthy control subjects and patients with mild/moderate COPD. Upregulation of apoptotic pathways, TGF-ß, TNF-{alpha}, and Fas in peripheral blood in patients with COPD was associated with increased T cell death (79). Future studies are needed to assess whether these systemic changes are present continuously as part of the stable state in COPD or reflect day-to-day variations in the inflammatory state.

In addition to increased levels of different proinflammatory cytokines, increased plasma levels of IL-8 (57, 68) and sICAM-1 (26, 57) have been are reported. These observations are in contrast to other reports of decreased plasma sICAM-1 in patients with COPD and indicate that there is poor evidence for an impaired endothelial cellular function in patients with COPD (51).


   ORIGIN OF SYSTEMIC INFLAMMATION
TOP
 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
 REFERENCES
 
The origin of the systemic inflammation present in patients with COPD remains poorly understood, and several (independent) pathways may be involved. As smoking causes many important extrapulmonary effects, like cardiovascular diseases, tobacco smoke alone may contribute significantly to systemic inflammation in COPD. In this respect, both systemic oxidative stress and peripheral vascular endothelial dysfunction were reported in passive smokers and in smokers with only few pack-years (80, 81). A second possible mechanism is the involvement of the local pulmonary inflammatory response in systemic inflammation, which was investigated recently by Vernooy and coworkers in patients with mild-to-moderate COPD (21). Comparison of levels of sTNF-R or IL-8 in sputum and plasma did not reveal direct correlations, thereby suggesting that the systemic inflammatory response in mild-to-moderate COPD is not due to an overflow of inflammatory mediators from the pulmonary compartment but, rather, that the inflammatory processes in the local and systemic compartment are regulated differently. Further evidence for the hypothesis that the inflammatory processes in the airways and the systemic circulation are independent processes comes from recent studies of Michel and colleagues (82). Healthy subjects exposed to inhalation of the proinflammatory bacterial product, lipopolysaccharide, showed differential changes in body temperature, airway reactivity, and FEV1. Subjects with elevated body temperature showed an increase systemic inflammatory response, whereas those with an airways hyperreactivity showed an increased airway inflammation but no systemic inflammation. Lipopolysaccharide-induced increases in body temperature and airways reactivity were not associated in any given subject, suggesting that the underlying mechanisms are independent.

A third pathway involved in the process of systemic inflammation could be related to hypoxia, a recurrent problem in COPD. As studies in vitro have revealed that hypoxia results in enhanced cytokine production by macrophages, the systemic hypoxemia observed in patients with COPD may contribute to the activation of the TNF system. Indeed, significant inverse correlations between PaO2 and circulating TNF-{alpha} and sTNF-R levels in patients with COPD were reported (75). Similarly, a significant relationship was found between the reduced oxygen delivery and the TNF-{alpha} levels in the peripheral circulation, stressing the role of tissue hypoxia (85).

Because the ability to maintain oxygen homeostasis is essential to survival, physiological systems have evolved to ensure the optimal oxygenation of all cells in each organism. Hypoxia-inducible factor (HIF)-1{alpha} plays a central and general role by signaling the existence of hypoxia to the transcriptional machinery in the nucleus of all cells. HIF-1 activates a number of target genes whose products are involved in angiogenesis, energy metabolism, erythropoiesis, inflammation, cell proliferation, vascular remodeling, and vasomotor responses (84). HIF-1 plays a major role in mediating pulmonary vascular remodeling in response to chronic hypoxia, and several HIF-1 target genes may be involved in these processes. (The role of HIF-1 in pulmonary vascular responses to chronic hypoxia and COPD is reviewed by Semenza in this issue [pp. 68–70].)

Interestingly, HIF-1{alpha} expression in the lung is regulated by the inspired oxygen concentration (85). Alveolar hypoxia in COPD can be related to hypoventilation or disturbances in pulmonary ventilation/perfusion matching. Recently, it was demonstrated that periods of even moderate hypoxia results in a mild lung injury characterized by the accumulation of macrophages, modest neutrophil influx, and accumulation of extravascular albumin. On the level of inflammatory mediators, DNA-binding activity of NF-{kappa}B and expression of mRNA for HIF-1{alpha}, TNF{alpha}, ICAM-1, MCP-1 and macrophage inflammatory protein (MIP)-1ß were increased (86). Alveolar macrophages appear to have a prominent role in the inflammatory response in hypoxia-induced lung injury and the related upregulation of inflammatory mediators.

Based on the observation of decreased antioxidative capacity of skeletal muscles in COPD (87), Rabinovich and coworkers have demonstrated an abnormal cytokine response to moderate exercise in patients with COPD (88). Plasma TNF-{alpha} levels, but not levels of sTNF-Rs and IL-6, rose consistently before and after training intervention. Recently, it was reported that local muscle exercise, despite the increased oxidative stress, did not result in changes in plasma cytokine levels (89). Further research is needed to clarify the origin and physiological significance of these exercise-related inflammatory responses in COPD.


   THE INTRICATE INTERFACE BETWEEN THE IMMUNE SYSTEM AND METABOLISM
TOP
 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
CONCLUSIONS
 REFERENCES
 
Metabolism controls production, maintenance and destruction of biomolecules and, more importantly, how energy is made available to organisms. In recent years, it has become evident that the control of orexigenic and anorexigenic circuits not only affects the regulation of body weight but also dramatically influences other important physiologic functions including immune homeostasis. It has also become clear that the adipose tissue can produce hormones and cytokines that significantly affect both energy status and immune responsiveness. These adipocyte-derived molecules that bridge metabolism and immune homeostasis are called adipokines. The growing family of the adipokines includes leptin, IL-1, IL-6, IL-8, IFN-{gamma}, TNF-{alpha}, TGF-ß, leukemia-inhibiting factor, and chemokines such as MCP-1 and MIP-1 (90–92).

Leptin
Leptin is a typical adipokine produced in proportion to the total body fat mass. A major role of leptin is to gauge the total amount of body fat, which indirectly reflects food availability, to stop food intake and to increase basal metabolism (93). In addition to the relationship between leptin levels and body fat in COPD, a blunted diurnal leptin response as well as a relationship between systemic inflammation and leptin levels particularly in emphysema patients has been reported (77, 94, 95). Leptin is classically considered as a hormone because it regulates the balance between food intake and energy expenditure, signaling to the brain the changes in stored energy. Leptin as a hormone influences directly the hypothalamo-pituitary-adrenal axis, the reproductive system, hematopoiesis, and angiogenesis (96).

Leptin is similar structurally to cytokines of the type I cytokine family, which are characterized by a long-chain four-helical bundle, and which include growth hormone, prolactin, erythropoietin, IL-3, IL-11, IL-12, oncostatin M, and G-CSF (97). Leptin levels are increased markedly in response to acute infection and sepsis, wherein it exerts direct effects on CD4+ T lymphocyte proliferation, macrophage phagocytosis, and secretion of inflammatory mediators such as IL-1 and TNF-{alpha} (96, 98). Leptin has been shown to affect both the innate and adaptive immune responses, and to stimulate the Th1 inflammatory response. At a central level, leptin affects thymic function and the generation of naïve T cells as well as their proliferation and secretion of IL-2. In the periphery, the presence of leptin promotes the generation of Th1 responses after CD4+ T cells have encountered an antigen (96). Increased levels of leptin in peripheral circulation of patients with COPD suffering from an acute exacerbation have been reported (99). Interestingly, recent data demonstrate that colon epithelial cells are a source of luminal leptin, which activates NF-{kappa}B, implicating further that leptin is a proinflammatory cytokine (100).

Glucose Metabolism and T Cell Activation and Tolerance
A rapid and sustained increase of cellular metabolic rate is required to support T lymphocyte proliferation, differentiation, and effector functions. Access to nutrients through increased expression of glucose transporters and activation of glycolysis is an important way through which costimulatory receptors can stimulate T cell growth, and T cells increase glucose uptake and glycolysis during immune responses (101). Another metabolic event affecting T cell responsiveness is the catabolism of the essential amino acid tryptophan (102).

Transcription Factors at the Interface between Metabolism and Immune Function
Transcription factors that are important in the homeostasis of lipid metabolism and immune responses include the peroxisome proliferator–activated receptors (PPAR), members of the nuclear receptor superfamily of ligand-activated transcriptional factors (103). To date, three mammalian PPARs have been isolated: PPAR{alpha}, PPAR{delta}, and PPAR{gamma}. While PPAR{alpha} is expressed in brown adipose tissue, liver heart, kidney, and stomach mucosa, PPAR{gamma} is found primarily in the adipose tissue, where it contributes to the differentiation of adipocytes (103). PPAR{delta} is expressed almost ubiquitously. Recently, PPAR{alpha} and PPAR{gamma} were reported to be important immunomodulatory mediators. In T cells, PPAR{alpha} negatively regulates the transcription of T-bet, a pivotal transcription factor for the expression of Th1 cytokines (104). Recent experiments showed that the PPAR{gamma} ligand, prostaglandin J2, can inhibit the production of nitric oxide, TNF-{alpha}, IL-1, and IL-6 from monocyte and/or macrophages as well as IL-2 and IFN-{gamma} from autoreactive T cells (105, 106). Upregulation of PPAR{gamma} ligands correlates with the amelioration of a variety of inflammatory conditions. Interestingly, the expression of PPAR{alpha} and PPAR{gamma}, but not of PPAR{delta}, was demonstrated recently on human airway smooth muscle cells (107). Activation of PPAR{gamma} had profound antiinflammatory effects and, remarkably, inhibited a corticosteroid-insensitive proinflammatory response at the level of both survival factor release and cell proliferation (107).


   CONCLUSIONS
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 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
REFERENCES
 
COPD is a complex systemic disorder characterized local pulmonary inflammation in addition to systemic inflammation, with possible superimposed effects of alveolar and tissue hypoxia. More research on the underlying cellular and molecular mechanisms is needed in order to discover new therapeutic targets for this prevalent, serious disorder for which no effective preventative therapy currently exists. The impact of systemic changes on morbidity and mortality in COPD stresses the role of nonpulmonary manifestations in this multicomponent disorder. The prominent role of HIF-1 and a better knowledge of the intricate network of interactions among energy regulation, immune surveillance, and vital organ functions could lead to future, valuable strategies for therapeutic intervention.


   FOOTNOTES
 
Conflict of Interest Statement: E.F.M.W. received a research grant from GlaxoSmithKline in 2002 ($250,000), a research grant from Boehringer Ingelheim in 2003 ($400,000), and a research grant from AstraZeneca in 2001 ($300,000).

(Received in original form August 12, 2004; accepted in final form September 30, 2004)


   REFERENCES
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 ABSTRACT
 PULMONARY INFLAMMATION IN COPD
 SYSTEMIC INFLAMMATION IN COPD
 ORIGIN OF SYSTEMIC INFLAMMATION
 THE INTRICATE INTERFACE BETWEEN...
 CONCLUSIONS
 REFERENCES
 

  1. Pauwels R, Buist AS, Calverley PMA, Jenkins CR, Hurd SS, on behalf of the GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI / WHO Global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163:1256–1276.[Free Full Text]
  2. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Lung Disease. NHLBI/WHO workshop report. Bethesda, National Heart, Lung and Blood Institute, April 2001; Update of the Management Sections, Gold website (www.goldcopd.com). Date updated: July 2003.
  3. Saetta M, Di Stefano A, Maestrelli P, Ferraresso A, Drigo R, Potena A, Ciaccia A, Fabbri LM. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis 1993;147:301–306.[Medline]
  4. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the peripheral airways of young cigarette smokers. N Engl J Med 1974;291:755–758.[Medline]
  5. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.[Abstract]
  6. Di Stefano A, Turato G, Maestrelli P, Mapp CE, Ruggieri MP, Roggeri A, Boschetto P, Fabbri LM, Saetta M. Airflow limitation in chronic bronchitis is associated with T-lymphocyte and macrophage infiltration of the bronchial mucosa. Am J Respir Crit Care Med 1996;153:629–632.[Abstract]
  7. O'Shaughnessy TC, Ansari TW, Barnes NC, Jeffery PK. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1. Am J Respir Crit Care Med 1997;155:852–857.[Abstract]
  8. Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, Maestrelli P, Ciaccia A, Fabbri LM. CD8+ T-lymphocytes in the peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;157:822–826.[Abstract/Free Full Text]
  9. Saetta M, Baraldo S, Corbino L, Turato G, Braccioni F, Rea F, Cavallesco G, Tropeano G, Mapp CE, Maestrelli P, et al. CD8+ cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:711–717.[Abstract/Free Full Text]
  10. Peinado VI, Barberà JA, Abate P, Ramirez J, Roca J, Santos S, Rodriguez-Roisin R. Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1605–1611.[Abstract/Free Full Text]
  11. Saetta M, Turato G, Facchini FM, Corbino L, Lucchini RE, Casoni G, Maestrelli P, Mapp CE, Ciaccia A, Fabbri LM. Inflammatory cells in the bronchial glands of smokers with chronic bronchitis. Am J Respir Crit Care Med 1997;156:1633–1639.[Abstract/Free Full Text]
  12. Zhu J, Majumdar S, Qiu Y, Ansari T, Oliva A, Kips JC, Pauwels RA, De Rose V, Jeffery PK. Interleukin-4 and interleukin-5 gene expression and inflammation in the mucus-secreting glands and subepithelial tissue of smokers with chronic bronchitis: lack of relationship with CD8+ cells. Am J Respir Crit Care Med 2001;164:2220–2228.[Abstract/Free Full Text]
  13. Baraldo S, Turato G, Badin C, Bazzan E, Beghe B, Zuin R, Calabrese F, Casoni G, Maestrelli P, Papi A, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004;59:308–312.[Abstract/Free Full Text]
  14. Stanescu D, Sanna A, Veriter C, Kostianev S, Calcagni PG, Fabbri LM, Maestrelli P. Airways obstruction, chronic expectoration, and rapid decline of FEV1 in smokers are associated with increased levels of sputum neutrophils. Thorax 1996;51:267–271.[Abstract]
  15. Maestrelli P, Calcagni PG, Saetta M, Bertin T, Mapp CE, Sanna A, Veriter C, Fabbri LM, Stanescu D. Integrin upregulation on sputum neutrophils in smokers with chronic airway obstruction. Am J Respir Crit Care Med 1996;154:1296–1300.[Abstract]
  16. Domagala-Kulawik J, Maskey-Warzechowska M, Kraszewska I, Chazan R. The cellular composition and macrophage phenotype in induced sputum in smokers and ex-smokers with COPD. Chest 2003;123:1054–1059.[Abstract/Free Full Text]
  17. Retamales I, Elliott WM, Meshi B, Coxson HO, Pare PD, Sciurba FC, Rogers RM, Hayashi S, Hogg JC. Amplification of inflammation in emphysema and its association with latent adenoviral infection. Am J Respir Crit Care Med 2001;164:469–473.[Abstract/Free Full Text]
  18. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996;14:397–440.[CrossRef][Medline]
  19. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001;19:163–196.[CrossRef][Medline]
  20. McDermott MF. TNF and TNFR biology in health and disease. Cell Mol Biol (Noisy-le-grand) 2001;47:619–635.
  21. Vernooy JH, Kucukaycan M, Jacobs JA, Chavannes NH, Buurman WA, Dentener MA, Wouters EF. Local and systemic inflammation in patients with chronic obstructive pulmonary disease: soluble tumor necrosis factor receptors are increased in sputum. Am J Respir Crit Care Med 2002;166:1218–1224.[Abstract/Free Full Text]
  22. Bresser P, Out TA, van Alphen L, Jansen HM, Lutter R. Airway inflammation in nonobstructive and obstructive chronic bronchitis with chronic haemophilus influenzae airway infection: comparison with noninfected patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:947–952.[Abstract/Free Full Text]
  23. Santos S, Peinado VI, Ramirez J, Morales-Blanhir J, Bastos R, Roca J, Rodriguez-Roisin R, Barbera JA. Enhanced expression of vascular endothelial growth factor in pulmonary arteries of smokers and patients with moderate chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:1250–1256.[Abstract/Free Full Text]
  24. Bucchioni E, Kharitonov SA, Allegra L, Barnes PJ. High levels of interleukin-6 in the exhaled breath condensate of patients with COPD. Respir Med 2003;97:1299–1302.[CrossRef][Medline]
  25. Patel IS, Roberts NJ, Lloyd-Owen SJ, Sapsford RJ, Wedzicha JA. Airway epithelial inflammatory responses and clinical parameters in COPD. Eur Respir J 2003;22:94–99.[Abstract/Free Full Text]
  26. Riise GC, Larsson S, Lofdahl CG, Andersson BA. Circulating cell adhesion molecules in bronchial lavage and serum in COPD patients with chronic bronchitis. Eur Respir J 1994;7:1673–1677.[Abstract]
  27. Di Stefano A, Maestrelli P, Roggeri A, Turato G, Calabro S, Potena A, Mapp CE, Ciaccia A, Covacev L, Fabbri LM, et al. Upregulation of adhesion molecules in the bronchial mucosa of subjects with chronic obstructive bronchitis. Am J Respir Crit Care Med 1994;149:803–810.[Abstract]
  28. Takanashi S, Hasegawa Y, Kanehira Y, Yamamoto K, Fujimoto K, Satoh K, Okamura K. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers. Eur Respir J 1999;14:309–314.[Abstract]
  29. Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 1987;84:5788–5792.[Abstract/Free Full Text]
  30. Allen JB, Manthey CL, Hand AR, Ohura K, Ellingsworth L, Wahl SM. Rapid onset of synovial inflammation and hyperplasia induced by transforming growth factor-ß. J Exp Med 1990;171:231–247.[Abstract/Free Full Text]
  31. Adams DH, Hathaway M, Shaw J, Burnett D, Elias E, Strain AJ. Transforming growth factor-{alpha} induces human T lymphocyte migration in vitro. J Immunol 1991;147:609–612.[Abstract]
  32. Gruber BL, Marchese MJ, Kew RR. Transforming growth factor-ß1 mediates mast cell chemotaxis. J Immunol 1994;152:5860–5867.[Abstract]
  33. de Boer WI, van Schadewijk A, Sont JK, Sharma HS, Stolk J, Hiemstra PS, van Krieken JH. Transforming growth factor-ß1 and recruitment of macrophages and mast cells in airways in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1951–1957.[Abstract/Free Full Text]
  34. Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, Okada Y, Yamasawa F, Nakahara K, Umeda A. Increased expression of transforming growth factor-ß1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). Am J Respir Crit Care Med 2001;163:1476–1483.[Abstract/Free Full Text]
  35. McCrea KA, Ensor JE, Nall K, Bleecker ER, Hasday JD. Altered cytokine regulation in the lungs of cigarette smokers. Am J Respir Crit Care Med 1994;150:696–703.[Abstract]
  36. Jatakanon A, Lalloo UG, Lim S, Chung KF, Barnes PJ. Increased neutrophils and cytokines, TNF-alpha and IL-8, in induced sputum of non-asthmatic patients with chronic dry cough. Thorax 1999;54:234–237.[Abstract/Free Full Text]
  37. de Boer WI, Sont JK, van Schadewijk A, Stolk J, van Krieken JH, Hiemstra PS. Monocyte chemoattractant protein 1, interleukin 8, and chronic airways inflammation in COPD. J Pathol 2000;190:619–626.[CrossRef][Medline]
  38. Beeh KM, Kornmann O, Buhl R, Culpitt SV, Giembycz MA, Barnes PJ. Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4. Chest 2003;123:1240–1247.[Abstract/Free Full Text]
  39. Becker S, Quay J, Koren HS, Haskill JS. Constitutive and stimulated MCP-1, GRO-alpha, -beta, and -gamma expression in human airway epithelium and bronchoalveolar macrophages. Am J Physiol Lung Cell Mol Physiol 1994;266:L278–L286.[Abstract/Free Full Text]
  40. Jinquan T, Frydenberg J, Mukaida N, Bonde J, Larsen CG, Matsushima K, Thestrup-Pedersen K. Recombinant human growth-regulated oncogene-alpha induces T lymphocyte chemotaxis: a process regulated via IL-8 receptors by IFN-gamma, TNF-alpha, IL-4, IL-10, and IL-13. J Immunol 1995;155:5359–5368.[Abstract]
  41. Li J, Thornhill MH. Growth-regulated peptide-{alpha} (GRO{alpha}) production by oral keratinocytes: a comparison with skin keratinocytes. Cytokine 2000;12:1409–1413.[CrossRef][Medline]
  42. Traves SL, Culpitt SV, Russell RE, Barnes PJ, Donnelly LE. Increased levels of the chemokines GRO{alpha} and MCP-1 in sputum samples from patients with COPD. Thorax 2002;57:590–595.[Abstract/Free Full Text]
  43. Saetta M, Mariani M, Panina-Bordignon P, Turato G, Buonsanti C, Baraldo S, Bellettato CM, Papi A, Corbetta L, Zuin R, et al. Increased expression of the chemokine receptor CXCR3 and its ligand CXCL10 in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002;165:1404–1409.[Abstract/Free Full Text]
  44. Hardaker EL, Bacon AM, Carlson K, Roshak AK, Foley JJ, Schmidt DB, Buckley PT, Comegys M, Panettieri RA Jr, Sarau HM, et al. Regulation of TNF-{alpha}- and IFN-{gamma}-induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease. FASEB J 2004;18:191–193.[Abstract/Free Full Text]
  45. John M, Au BT, Jose PJ, Lim S, Saunders M, Barnes PJ, Mitchell JA, Belvisi MG, Chung KF. Expression and release of interleukin-8 by human airway smooth muscle cells: inhibition by Th-2 cytokines and corticosteroids. Am J Respir Cell Mol Biol 1998;18:84–90.[Abstract/Free Full Text]
  46. Clarke DL, Patel HJ, Mitchell JA, Yacoub MH, Giembycz MA, Belvisi MG. Regulation of the release of colony-stimulating factors from human airway smooth muscle cells by prostaglandin E2 [abstract]. Br J Pharmacol 2001;133:40P.
  47. Colotta F, Re F, Polentarutti N, Sozzani S, Mantovani A. Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products. Blood 1992;80:2012–2020.[Abstract/Free Full Text]
  48. Cassatella MA, Gasperini S, Calzetti F, Bertagnin A, Luster AD, Mc-Donald PP. Regulated production of the interferon-gamma-inducible protein-10 (IP-10) chemokine by human neutrophils. Eur J Immunol 1997;27:111–115.[Medline]
  49. Gasperini S, Marchi M, Calzetti F, Laudanna C, Vicentini L, Olsen H, Murphy M, Liao F, Farber J, Cassatella MA. Gene expression and production of the monokine induced by IFN-{gamma} (MIG), IFN-inducible T cell alpha chemoattractant (I-TAC), and IFN-{gamma}-inducible protein-10 (IP-10) chemokines by human neutrophils. J Immunol 1999;162:4928–4937.[Abstract/Free Full Text]
  50. Romagnani P, Lasagni L, Annunziato F, Serio M, Romagnani S. CXC chemokines: the regulatory link between inflammation and angiogenesis. Trends Immunol 2004;25:201–209.[CrossRef][Medline]
  51. Noguera A, Busquets X, Sauleda J, Villaverde JM, MacNee W, Agusti AG. Expression of adhesion molecules and G proteins in circulating neutrophils in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998;158:1664–1668.[Abstract/Free Full Text]
  52. Noguera A, Batle S, Miralles C, Iglesias J, Busquets X, MacNee W, Agusti AG. Enhanced neutrophil response in chronic obstructive pulmonary disease. Thorax 2001;56:432–437.[Abstract/Free Full Text]
  53. Burnett D, Chamba A, Hill SL, Stockley RA. Neutrophils from subjects with chronic obstructive lung disease show enhanced chemotaxis and extracellular proteolysis. Lancet 1987;2:1043–1046.[Medline]
  54. Burnett D, Chamba A, Hill SL, Stockley RA. Effects of plasma, tumour necrosis factor, endotoxin and dexamethasone on extracellular proteolysis by neutrophils from healthy subjects and patients with emphysema. Clin Sci (Lond) 1989;77:35–41.[Medline]
  55. Cataldo D, Munaut C, Noel A, Frankenne F, Bartsch P, Foidart JM, Louis R. Matrix metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics. Allergy 2001;56:145–151.[CrossRef][Medline]
  56. Sauleda J, Garcia-Palmer FJ, Gonzalez G, Palou A, Agusti AG. The activity of cytochrome oxidase is increased in circulating lymphocytes of patients with chronic obstructive pulmonary disease, asthma, and chronic arthritis. Am J Respir Crit Care Med 2000;161:32–35.[Abstract/Free Full Text]
  57. Hageman GJ, Larik I, Pennings HJ, Haenen GR, Wouters EF, Bast A. Systemic poly(ADP-ribose) polymerase-1 activation, chronic inflammation, and oxidative stress in COPD patients. Free Radic Biol Med 2003;35:140–148.[Medline]
  58. Das SK, Berger NA. Alterations in deoxynucleoside triphosphate metabolism in DNA-damaged cells: identification and consequences of poly(ADP-ribose) olymerase-dependent and –independent processes. Biochem Biophys Res Commun 1986;137:1153–1158.[CrossRef][Medline]
  59. Miller LG, Goldstein G, Murphy M, Ginns LC. Reversible alterations in immunoregulatory T cells in smoking: analysis by monoclonal antibodies and flow cytometry. Chest 1982;82:526–529.[Abstract/Free Full Text]
  60. Costabel U, Bross KJ, Reuter C, Ruhle KH, Matthys H. Alterations in immunoregulatory T-cell subsets in cigarette smokers: a phenotypic analysis of bronchoalveolar and blood lymphocytes. Chest 1986;90:39–44.[Abstract/Free Full Text]
  61. Ekberg-Jansson A, Andersson B, Avra E, Nilsson O, Lofdahl CG. The expression of lymphocyte surface antigens in bronchial biopsies, bronchoalveolar lavage cells and blood cells in healthy smoking and never-smoking men, 60 years old. Respir Med 2000;94:264–272.[CrossRef][Medline]
  62. Ekberg-Jansson A, Arva E, Nilsson O, Lofdahl CG, Andersson B. A comparison of the expression of lymphocyte activation markers in blood, bronchial biopsies and bronchoalveolar lavage: evidence for an enrichment of activated T lymphocytes in the bronchoalveolar space. Respir Med 1999;93:563–570.[CrossRef][Medline]
  63. de Jong JW, van der Belt-Gritter B, Koeter GH, Postma DS. Peripheral blood lymphocyte cell subsets in subjects with chronic obstructive pulmonary disease: association with smoking, IgE and lung function. Respir Med 1997;91:67–76.[CrossRef][Medline]
  64. Aldonyte R, Jansson L, Piitulainen E, Janciauskiene S. Circulating monocytes from healthy individuals and COPD patients. Respir Res 2003;4:11.[CrossRef][Medline]
  65. Rahman I, Morrison D, Donaldson K, MacNee W. Systemic oxidative stress in asthma, COPD, and smokers. Am J Respir Crit Care Med 1996;154:1055–1060.[Abstract]
  66. Rahman I, Swarska E, Henry M, Stolk J, MacNee W. Is there any relationship between plasma antioxidant capacity and lung function in smokers and in patients with chronic obstructive pulmonary disease? Thorax 2000;55:189–193.[Abstract/Free Full Text]
  67. Pratico D, Basili S, Vieri M, Cordova C, Violi F, Fitzgerald GA. Chronic obstructive pulmonary disease is associated with an increase in urinary levels of isoprostane F2alpha-III, an index of oxidant stress. Am J Respir Crit Care Med 1998;158:1709–1714.[Abstract/Free Full Text]
  68. Schols AM, Buurman WA, Staal van den Brekel AJ, Dentener MA, Wouters EF. Evidence for a relation between metabolic derangements and increased levels of inflammatory mediators in a subgroup of patients with chronic obstructive pulmonary disease. Thorax 1996;51:819–824.[Abstract]
  69. Creutzberg EC, Schols AM, Weling-Scheepers CA, Buurman WA, Wouters EF. Characterization of nonresponse to high caloric oral nutritional therapy in depleted patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:745–752.[Abstract/Free Full Text]
  70. Dahl M, Tybjaerg-Hansen A, Vestbo J, Lange P, Nordestgaard BG. Elevated plasma fibrinogen associated with reduced pulmonary function and increased risk of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1008–1011.[Abstract/Free Full Text]
  71. Dentener MA, Vreugdenhil AC, Hoet PH, Vernooy JH, Nieman FH, Heumann D, Janssen YM, Buurman WA, Wouters EF. Production of the acute-phase protein lipopolysaccharide-binding protein by respiratory type II epithelial cells: implications for local defense to bacterial endotoxins. Am J Respir Cell Mol Biol 2000;23:146–153.[Abstract/Free Full Text]
  72. Eid AA, Ionescu AA, Nixon LS, Lewis-Jenkins V, Matthews SB, Griffiths TL, Shale DJ. Inflammatory response and body composition in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1414–1418.[Abstract/Free Full Text]
  73. Di Francia M, Barbier D, Mege JL, Orehek J. Tumor necrosis factor-{alpha} levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;150:1453–1455.[Abstract]
  74. Yasuda N, Gotoh K, Minatoguchi S, Asano K, Nishigaki K, Nomura M, Ohno A, Watanabe M, Sano H, Kumada H, et al. An increase of soluble Fas, an inhibitor of apoptosis, associated with progression of COPD. Respir Med 1998;92:993–999.[CrossRef][Medline]
  75. Takabatake N, Nakamura H, Abe S, Inoue S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. The relationship between chronic hypoxemia and activation of the tumor necrosis factor-{alpha} system in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1179–1184.[Abstract/Free Full Text]
  76. Dentener MA, Creutzberg EC, Schols AM, Mantovani A, van't Veer C, Buurman WA, Wouters EF. Systemic anti-inflammatory mediators in COPD: increase in soluble interleukin 1 receptor II during treatment of exacerbations. Thorax 2001;56:721–726.[Abstract/Free Full Text]
  77. Takabatake N, Nakamura H, Abe S, Hino T, Saito H, Yuki H, Kato S, Tomoike H. Circulating leptin in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;159:1215–1219.[Abstract/Free Full Text]
  78. Porteu F, Nathan C. Shedding of tumor necrosis factor receptors by activated human neutrophils. J Exp Med 1990;172:599–607.[Abstract/Free Full Text]
  79. Hodge SJ, Hodge GL, Reynolds PN, Scicchitano R, Holmes M. Increased production of TGF-ß and apoptosis of T lymphocytes isolated from peripheral blood in COPD. Am J Physiol Lung Cell Mol Physiol 2003;285:L492–L499.[Abstract/Free Full Text]
  80. Dietrich M, Block G, Hudes M, Morrow JD, Norkus EP, Traber MG, Cross CE, Packer L. Antioxidant supplementation decreases lipid peroxidation biomarker F2-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev 2002;11:7–13.[Abstract/Free Full Text]
  81. Dietrich M, Block G, Benowitz NL, Morrow JD, Hudes M, Jacob P III, Norkus EP, Packer L. Vitamin C supplementation decreases oxidative stress biomarker f2-isoprostanes in plasma of nonsmokers exposed to environmental tobacco smoke. Nutr Cancer 2003;45:176–184.[CrossRef][Medline]
  82. Michel O, Dentener M, Corazza F, Buurman W, Rylander R. Healthy subjects express differences in clinical responses to inhaled lipopolysaccharide that are related with inflammation and with atopy. J Allergy Clin Immunol 2001;107:797–804.[CrossRef][Medline]
  83. Pitsiou G, Kyriazis G, Hatzizisi O, Argyropoulou P, Mavrofridis E, Patakas D. Tumor necrosis factor-{alpha} serum levels, weight loss and tissue oxygenation in chronic obstructive pulmonary disease. Respir Med 2002;96:594–598.[CrossRef][Medline]
  84. Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000;88:1474–1480.[Abstract/Free Full Text]
  85. Yu AY, Frid MG, Shimoda LA, Wiener CM, Stenmark K, Semenza GL. Temporal, spatial, and oxygen-regulated expression of hypoxia-inducible factor-1 in the lung. Am J Physiol Lung Cell Mol Physiol 1998;275:L818–L826.[Abstract/Free Full Text]
  86. Madjdpour C, Jewell UR, Kneller S, Ziegler U, Schwendener R, Booy C, Klausli L, Pasch T, Schimmer RC, Beck-Schimmer B. Decreased alveolar oxygen induces lung inflammation. Am J Physiol Lung Cell Mol Physiol 2003;284:L360–L367.[Abstract/Free Full Text]
  87. Engelen MP, Orozco-Levi M, Deutz NE, Barreiro E, Hernandez N, Wouters EF, Gea J, Schols AM. Glutathione and glutamate levels in the diaphragm of patients with chronic obstructive pulmonary disease. Eur Respir J 2004;23:545–551.[Abstract/Free Full Text]
  88. Rabinovich RA, Ardite E, Troosters T, Carbo N, Alonso J, Gonzalez de Suso JM, Vilaro J, Barbera JA, Polo MF, Argiles JM, et al. Reduced muscle redox capacity after endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;164:1114–1118.[Abstract/Free Full Text]
  89. Koechlin C, Couillard A, Cristol JP, Chanez P, Hayot M, Le Gallais D, Prefaut C. Does systemic inflammation trigger local exercise-induced oxidative stress in COPD? Eur Respir J 2004;23:538–544.[Abstract/Free Full Text]
  90. Bruun JM, Pedersen SB, Kristensen K, Richelsen B. Effects of proinflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro. Mol Cell Endocrinol 2002;190:91–99.[CrossRef][Medline]
  91. Gerhardt CC, Romero IA, Cancello R, Camoin L, Strosberg AD. Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol 2001;175:81–92.[CrossRef][Medline]
  92. Matarese G, La Cava A. The intricate interface between immune system and metabolism. Trends Immunol 2004;25:193–200.[CrossRef][Medline]
  93. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763–770.[CrossRef][Medline]
  94. Schols AM, Creutzberg EC, Buurman WA, Campfield LA, Saris WH, Wouters EF. Plasma leptin is related to proinflammatory status and dietary intake in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160:1220–1226.[Abstract/Free Full Text]
  95. Takabatake N, Nakamura H, Minamihaba O, Inage M, Inoue S, Kagaya S, Yamaki M, Tomoike H. A novel pathophysiologic phenomenon in cachexic patients with chronic obstructive pulmonary disease: the relationship between the circadian rhythm of circulating leptin and the very low-frequency component of heart rate variability. Am J Respir Crit Care Med 2001;163:1314–1319.[Abstract/Free Full Text]
  96. La Cava A, Alviggi C, Matarese G. Unraveling the multiple roles of leptin in inflammation and autoimmunity. J Mol Med 2004;82:4–11.[CrossRef][Medline]
  97. Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, et al. Crystal structure of the obese protein leptin-E100. Nature 1997;387:206–209.[CrossRef][Medline]
  98. Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, et al. Leptin regulates proinflammatory immune responses. FASEB J 1998;12:57–65.[Abstract/Free Full Text]
  99. Creutzberg EC, Wouters EFM, vanderHoven-Augustin IML, Dentener MA, Schols AMWJ. Disturbances in leptin metabolism are related to energy imbalance during acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;162:1239–1245.[Abstract/Free Full Text]
  100. Sitaraman S, Liu X, Charrier L, Gu LH, Ziegler TR, Gewirtz A, Merlin D. Colonic leptin: source of a novel proinflammatory cytokine involved in IBD. FASEB J 2004;18:696–698.[Abstract/Free Full Text]
  101. Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell 2000;6:683–692.[CrossRef][Medline]
  102. Grohmann U, Fallarino F, Puccetti P. Tolerance, DCs and tryptophan: much ado about IDO. Trends Immunol 2003;24:242–248.[CrossRef][Medline]
  103. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409–435.[CrossRef][Medline]
  104. Jones DC, Ding X, Zhang TY, Daynes RA. Peroxisome proliferator-activated receptor alpha negatively regulates T-bet transcription through suppression of p38 mitogen-activated protein kinase activation. J Immunol 2003;171:196–203.[Abstract/Free Full Text]
  105. Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AE, Drew PD, Racke MK. Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-{Delta}(12,14)-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002;168:2508–2515.[Abstract/Free Full Text]
  106. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ. The nuclear receptor PPAR{gamma} and immunoregulation: PPAR{gamma} mediates inhibition of helper T cell responses. J Immunol 2000;164:1364–1371.[Abstract/Free Full Text]
  107. Patel HJ, Belvisi MG, Bishop-Bailey D, Yacoub MH, Mitchell JA. Activation of peroxisome proliferator-activated receptors in human airway smooth muscle cells has a superior anti-inflammatory profile to corticosteroids: relevance for chronic obstructive pulmonary disease therapy. J Immunol 2003;170:2663–2669.[Abstract/Free Full Text]