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The Proceedings of the American Thoracic Society 6:638-647 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200907-073DP
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Systemic and Local Inflammation in Asthma and Chronic Obstructive Pulmonary Disease

Is There a Connection?

Emiel F. M. Wouters1, Niki L. Reynaert1, Mieke A. Dentener1 and Juanita H. J. Vernooy1

1 NUTRIM School for Nutrition, Toxicology and Metabolism, Department of Respiratory Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands

Correspondence and requests for reprints should be addressed to Prof. Dr. E. F. M. Wouters, M.D., Ph.D., Maastricht University Medical Center + (MUMC+), Dept. of Respiratory Medicine, P.O. Box 5800 6202 AZ, Maastricht, The Netherlands. E-mail: e.wouters{at}mumc.nl

ABSTRACT

Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) and probably asthma are associated with low-grade systemic inflammatory changes. In patients with COPD, systemic inflammation is considered a key factor in the pathogenesis of the multicomponent disease manifestations. Spillover of inflammatory mediators into the circulation is generally considered to be the source of this systemic inflammation. Despite this attractive hypothesis, the nature of systemic inflammation in COPD and asthma remains unclear. Available scientific data challenge the spill-over hypothesis. Interventions with biologicals such as TNF-{alpha} do not modify local or systemic inflammation in these inflammatory respiratory diseases. Adipose tissue–mediated inflammation is discussed as a connecting link of systemic inflammation in asthma and COPD.

Key Words: COPD • asthma • local inflammation • systemic inflammation • adipocyte dysfunction

Asthma and chronic obstructive pulmonary disease (COPD) are the two most prevalent inflammatory lung disorders, and their incidence is rising globally. In both diseases, the local inflammation is chronic, but there are important differences in its location, inflammatory cell and mediator profiles, and response to therapy.

In patients with COPD, and even in smokers without airflow limitation, inflammation is found throughout the tracheobronchial tree (1, 2). T lymphocytes, with a preponderance of the CD8+ subtype, and macrophages are found in the walls of central and peripheral airways and in the parenchyma (3). The number of CD8+ cytotoxic T lymphocytes correlates well with the degree of airflow limitation in COPD, suggesting a pivotal role for this cell type in the pathophysiology of the disease, potentially through perforins and granzymes (4). CD8+ T cells are recruited to the lungs by the chemokines CXCL9, CXCL10, and CXCL11, which are elevated in sputum of patients with COPD and correlate with disease severity (5). These chemokines are induced by IFN-{gamma}. CD8+ T cells are a principal source of IFN-{gamma}, providing an important amplification loop. Neutrophils can be observed in airway lumen and parenchyma and also in bronchial glands, indicating a possible role in mucus hypersecretion (6). Neutrophils are recruited to the lungs by CXCL1 (Gro-{alpha}), CXCL8 (IL-8), and leukotriene B4, chemokines that are secreted by activated macrophages and that are present in elevated amounts in the sputum of patients with COPD compared with healthy control subjects (7). Neutrophils contain neutrophil elastase and matrix metallopeptidase (MMP)-9, two proteases that are believed to play a role in the development of emphysema. The number of neutrophils is increased in induced sputum of patients with COPD and correlates with disease severity (8). Enhanced numbers of macrophages are also a feature of the inflammatory response in COPD. Circulating monocytes are attracted to the lungs by the chemokines CCL2 and CXCL1 and then differentiate into macrophages (9). These macrophages provide a source of a myriad of mediators that orchestrate the inflammatory reaction. Mice that overexpress TNF-{alpha} spontaneously develop emphysema (10, 11), and Keatings and colleagues demonstrated that TNF-{alpha} is increased in induced sputum of patients with COPD (8, 12). We did not observe enhanced TNF-{alpha} levels but found the soluble TNF-{alpha} receptor 55 (sTNF-R55), which is considered a proinflammatory marker because its shedding is induced by inflammatory stimuli, to be increased in induced sputum and to show an inverse correlation with FEV1 (13).

In contrast to COPD, the inflammatory process in asthma is mainly restricted to the larger, conducting airways. As the disease worsens and becomes more chronic, inflammation can spread to smaller airways. Typically, asthma is considered an allergic disease, associated with eosinophilic airway inflammation. In recent years, it has become evident that 50% of patients with asthma display nonallergic, noneosinophilic asthma (14). This subpopulation of patients with asthma is characterized by neutrophilic inflammation. These patients often experience more severe asthma that does not respond to steroid treatment, whereas other patients have few signs of inflammation (15). In allergic asthma, activated mast cells and CD4+ Th2 cells are the predominant cell types after eosinophils (16). The Th2 type of inflammation is common to allergic diseases, and the Th2 cytokines IL-4 and IL-13 are involved in immunoglobulin class switching to IgE. IL-4 furthermore plays a role in the differentiation of uncommitted Th0 to Th2 cells, which are recruited by CCL17 and CCL22 that are secreted by airway epithelial and dendritic cells (17). Eosinophils are recruited to the airways of patients with asthma through the release of IL-5 by Th2 cells and CCL5, CCL11, CCL13, CCL24, and CCL26 by airway epithelium (18). The eosinophil contains important mediators such as major basic protein, eosinophil peroxidase and eosinophil cationic protein (ECP), cytokines, and chemokines (19). The number of eosinophils strongly correlates with disease severity (20), and treatment with corticosteroids dramatically reduces their numbers in conjunction with clinical improvement (21). Therefore, it was believed that eosinophils play a key role in asthma pathophysiology and consequently became a target for drug development. However, although eosinophil numbers were reduced in recent clinical trials with anti–IL-5, few effects on lung function were observed (22). This disappointing outcome could be due to the incomplete abrogation of eosinophilic infiltration or the possible involvement of eosinophils in tissue remodeling. Mast cells are another key cellular player in allergic asthma and are present in airway epithelium, in submucosa, and in proximity to airway smooth muscle (23). Their proliferation is induced by the Th2 cytokine IL-9, and they are recruited to the airways by CXCL8 and CXCL10 (24). Upon activation through IgE cross linking, mast cells release granule-associated mediators that include histamine, cytokines, and proteases and actively metabolize arachidonic acid to produce leukotrienes, prostaglandins, and thromboxanes. These mediators are important effectors of smooth muscle contraction and increased microvascular permeability and further perpetuate inflammatory cell influx (25). Examples of other important proinflammatory cytokines that are found in increased amounts in lungs of patients with asthma are TNF-{alpha}, TGF-β, IL-17, CCL11, and CCL5 (26–28). The sources of cytokines are plural, including epithelial cells and macrophages. Some cytokines, such as TNF-{alpha}, act as amplifiers of the inflammatory response through their ability to activate the transcription factor nuclear factor (NF)-{kappa}B, which is a key activator of gene expression of cytokines and chemokines. It has furthermore been demonstrated that inhalation of TNF-{alpha} can cause airway hyperresponsiveness (AHR) and can act directly on airway smooth muscle cells to enhance contractility in response to spasmogens (29).

EVIDENCE OF SYSTEMIC INFLAMMATION IN ASTHMA AND COPD

Systemic Inflammation in COPD
Many studies have reported various abnormalities in circulating inflammatory cells in patients with COPD. Circulating neutrophil numbers are not increased in patients with COPD, but there is an inverse correlation between FEV1 and the neutrophil numbers in the circulation (30). These data are confirmed more recently by Dentener and colleagues, who reported a significant relationship between the number of neutrophils in the circulation and FEV1 in smoking control subjects and in patients with COPD (31). Neutrophils from patients with COPD show an enhanced production of reactive oxygen species in response to stimulating agents. 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 clinically stable condition (32, 33).

Compared with control subjects, patients with stable disease showed an increased expression of CD11b/CD18 in circulating neutrophils and lower expression levels of ICAM-1. Increased plasma-soluble ICAM-1, a surrogate of its expression on the endothelium, has been reported by other researchers (34). In addition, the authors showed that blood neutrophils isolated from patients with COPD produced more reactive oxygen species under basal conditions and after stimulation in vitro as compared with neutrophils from smoking and nonsmoking control subjects, and this respiratory burst correlated with the elevated expression of adhesion molecules (33). Peripheral neutrophils isolated from patients with COPD showed enhanced chemotaxis and extracellular proteolysis in vitro (35, 36). In contrast, other researchers found no differences in the secretion of MMP9 by circulating granulocytes comparing patients with COPD and control subjects (37). 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 down-regulated irrespective of the clinical condition of the patient (32). However, the pathogenic implications of most of these findings are unclear and need confirmation in well-characterized patient groups and in different phases of the disease process.

Changes in circulating lymphocytes are difficult to interpret because they may reflect a recruitment of circulating lymphocytes into the lungs.

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 (38–41). In this respect, de Jong and coworkers (42) 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 (consisting of exsmokers and never-smokers), 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. An increase in apoptosis of peripheral T lymphocytes from patients with COPD with increased expression of Fas, TNF-{alpha}, and TGF-β has also been reported (43). A more recent study reports an increase in CD8+ cells, particularly those expressing Fas, indicating that there may be an increase in apoptosis of CD8+ T cells (44). Subset analysis has shown a slight increase in CD4+ cells expressing IFN-{gamma} and a decrease in cells expressing IL-4, indicating Th1 predominance in the peripheral circulation, with no changes in CD8+ cell subsets (45). Circulating {gamma}{delta} T cells are increased in normal smokers but not in patients with COPD (46).

Recent findings indicate abnormal circulating 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 (47) and was found to be significantly related to disease severity as reflected by the degree of airflow limitation. Hageman and colleagues (48) investigated activation of nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which forms extensive poly(ADP-ribose) polymers from its substrate nicotinamide adenine dinucleotide (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 (49).

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 MMP9 but less IL-8 than those from control subjects (50). 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 (50). 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 and are key players in innate immunity and reduction of inflammatory reactions. Increased levels of C-reactive protein (CRP) and lipopolysaccharide binding protein in patients with stable COPD were demonstrated particularly in patients with COPD (51) who had an increased resting energy expenditure and decreased fat-free mass.

In stable COPD, plasma concentrations of CRP are related to or cause mortality in patients with mild to moderate disease (52) but not in patients with severe and very severe disease (53). Increased CRP is also related to health status and exercise capacity and appears to be a significant predictor of body mass index (54). Although CRP is related to FEV1 in cross-sectional studies, there is no association with the progressive decline of FEV1 in longitudinal studies (55).

A prospective epidemiological study 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 (56). 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 able to produce acute-phase proteins (57).

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 (48, 58–61). The detection of biologically active TNF-{alpha} can be hampered by its short half-life (~6–7 min), the formation of complexes with both sTNF-R subtypes, and its renal clearance. Small but significant increases in circulating levels of sTNF-R55 and sTNF-R75 have been demonstrated in COPD (13, 51, 62–64). Because inflammatory stimuli such as TNF-{alpha} induce shedding of membrane-bound TNFR75, the enhanced levels of sTNF-R may reflect the enhanced inflammatory status of patients with COPD. Yasuda and colleagues investigated the association between apoptosis-related factors and the progression of COPD (60) and demonstrated that plasma levels of soluble Fas (CD95), an inhibitor of apoptosis, were increased significantly in patients with severe COPD when compared with healthy control subjects and patients with mild to smoderate COPD. Circulating CXCL8 concentrations have also been measured in patients with COPD (65), whereas IL-1β concentrations and concentrations of its endogenous IL-1 receptor antagonist have not been reported in COPD (66). 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 (48, 51) and sICAM-1 (34, 48) have been reported.

SYSTEMIC INFLAMMATION IN ASTHMA

In asthma, the evidence for systemic inflammation is scarcer than in COPD. Eosinophils are not only present in increased numbers in the lungs of patients with allergic asthma, but the number of peripheral-blood eosinophils is also elevated and related to disease severity and pulmonary function (20). In addition to the eosinophil itself, its granular proteins can be found in the circulation of patients with asthma as a marker for their activation. For instance, serum levels of ECP correlate well with the number of activated eosinophils in bronchial biopsies of patients with asthma (67, 68); ECP is therefore a potential systemic biomarker for airway inflammation. However, serum ECP does not seem to correlate with AHR (69, 70).

Blood inflammatory cell numbers have recently been used by Nadif and colleagues to study the heterogeneity of asthma and to describe subphenotypes (71). Using cut-off values for the number of blood eosinophils and neutrophils, they describe four inflammatory groups with their distinct clinical features. First, 43.6% of patients do not show marked systemic inflammation, which cannot solely be explained by the use of corticosteroids. In the second group, which consisted of patients with high numbers of blood eosinophils, IgE levels and AHR were high, whereas FEV1 was lower than in the other groups. Clinically, these patients reported more frequent asthma attacks and more severe symptoms. In patients who were characterized by high numbers of blood eosinophils and neutrophils, nocturnal symptoms were more frequent, and this group featured a relatively older population with a female preponderance. Last, patients with asthma who had only high numbers of blood neutrophils were more often smokers with a negative skin prick test. The high neutrophil number population reported more dyspnea, and when only considering nonsmokers in this subgroup, more chronic phlegm was also a clinical feature. This study not only highlights the association between systemic inflammation and asthma but also demonstrates the use of circulating granulocytes as a simple way to subphenotype asthma, which is feasible on a routine basis in the clinic.

A few studies have investigated the presence of an acute phase response in asthma. These studies demonstrated elevated serum levels of CRP in patients compared with healthy control subjects, but the association between asthma and CRP is not clear. A population-based study by Kony and colleagues found FEV1 to be lower and bronchial hyperresponsiveness to be more frequent in patients with asthma who had high CRP levels (72). A multicenter epidemiological study found increased levels of CRP only in nonallergic and not in allergic patients with asthma, but a positive correlation with total IgE was determined. This study also showed a significant relationship between increased CRP and respiratory symptoms such as wheeze, nocturnal cough, and breathlessness after effort, but, in contrast to the study of Kony and colleagues, no association of CRP with AHR was found (73). An association between high sensitivity CRP and nonallergic asthma was found, which remained significant after adjusting for age, sex, smoking, and body mass index. Lastly, Takamura and colleagues demonstrated in a cross-sectional study of a small group of patients with asthma that CRP levels were increased only in steroid-naive subjects and not in patients on inhaled steroids. In this group of patients with steroid-naive asthma, they showed in addition that CRP levels negatively correlated with indices of lung function and positively with sputum eosinophil counts (74). It would be interesting to investigate whether similar phenotypes to the study by Nadif and colleagues could be observed using CRP or whether CRP could help to further subphenotype the populations with asthma. Determinations of cytokine levels associated with the acute-phase response in plasma or in serum of patients with asthma have not been widely performed. Circulating IL-6 was significantly elevated in subjects with asthma compared with healthy control subjects and further increased after allergen challenge (75). Serum IL-6 was also found to be increased in patients with asthma by Higashimoto and colleagues, as were TNF-{alpha}, tissue inhibitor of metalloproteinases–1, and fibrinogen (76). In this study, 60% of control subjects had diabetes mellitus, which likely obscured differences and could explain the lack of difference in markers such as CRP.

SYSTEMIC AND LOCAL INFLAMMATION: A CONNECTION?

Systemic Inflammatory Response Induced by Exogenous Noxious Particles or Gases
Smoking and air pollution are important risk factors for the development of COPD. It is well established that cigarette smoke and particulate matter provoke a local inflammatory response in the respiratory system. After entering the blood, however, cigarette smoke and particulate matter may significantly contribute to or cause systemic inflammation, which was recently extensively reviewed (77–79). An integral component of the systemic inflammatory response is stimulation of the hematopoietic system, specifically the bone marrow, resulting in the release of leukocytes and platelets into the bloodstream. Human studies suggest that the bone marrow increases its output, predominantly polymorphonuclear leukocytes, when the lung is challenged by increasing concentrations of particles (80, 81), whereas its output is suppressed after exposure to low levels (82). Another key component in the systemic inflammatory response induced by cigarette smoke and particulate matter is systemic oxidative stress. Numerous markers for oxidative damage, such as oxidized or nitrated proteins and peroxidized polyunsaturated fatty acids and their degradation products, have been used to demonstrate that systemic oxidative stress is increased in humans exposed to smoke or an episode of air pollution. Also, an increase in endothelial dysfunction of peripheral vessels together with hemostatic and coagulation markers was reported after inhalation of cigarette smoke and particulate matter. Last, acute effects of cigarette smoking are suggested to affect the epithelial permeability in smokers (83).

Systemic "Spill-over"
It is unclear if there is a relationship between pulmonary and systemic inflammation in asthma and COPD. The development of inflammatory processes linked to pulmonary diseases is often thought to originate and to be maintained in the lung. This systemic "spill-over" of the pulmonary inflammatory response is hypothesized to result in a low-grade systemic inflammation. The absence of systemic inflammation in some patients and the persistence of systemic inflammation in the absence of smoke exposure (13) have challenged this concept. Otherwise, identification of the nature of systemic inflammation offers new targets for therapy. The concept of spill-over was for the first time investigated by Vernooy and colleagues in patients with mild to moderate COPD (13). Comparison of levels of soluble tumor necrosis factor receptors sTNF-R55 and sTNF-R75 or IL-8 in sputum and plasma did not reveal direct correlations, suggesting that the systemic inflammatory response in mild to moderate COPD does not result from a spill-over of inflammatory mediators from the pulmonary compartment but rather that the inflammatory processes in the local and systemic compartment are differently regulated. These data were confirmed by Zeng and colleagues (84). They also found no correlations between levels of TNF-{alpha}, sTNF-R55, or sTNF-R75 in plasma and induced sputum of smokers, nonsmokers, and patients with COPD after treatment for an exacerbation. Hurst and colleagues were not able to demonstrate any relationships between the inflammatory patterns in upper or lower airways and systemic compartment as assessed by serum IL-6 concentration (85). Their data also indicate that, in stable patients with COPD, the degree of systemic inflammation is independent of airway IL-8 concentration and bacterial colonization, again suggesting that the pulmonary and systemic responses may be modulated separately. Dentener and colleagues investigated the relationship between pulmonary and systemic inflammation in COPD in another way. They measured the spontaneous and LPS-induced production of TNF-{alpha} by sputum cells versus blood cells and demonstrated that sputum cells produced spontaneously high levels of TNF-{alpha} but were unresponsive to LPS. In contrast, blood cells produced only TNF-{alpha} in response to LPS, thereby suggesting an independent regulation of local versus systemic inflammation in COPD (31).

More recently, the concept of spill-over was assessed by using disease markers of surfactant protein-D (SP-D). The serum concentration of SP-D, a collectin family member synthesized and secreted by alveolar type II and nonciliated bronchiolar epithelial cells, has been proposed as noninvasive parameter to assess the permeability or integrity of the blood–airspace barrier in respiratory diseases. Recent data indeed showed that SP-D is increased in serum of patients with COPD (86), whereas bronchoalveolar lavage fluid (BALF) levels are known to be reduced (87). These data demonstrate that lung-derived inflammatory mediators can end up in the circulation. No correlation was found with the degree of emphysema, and no increase of SP-D levels was demonstrated with more progressive airflow limitation (86).

Koopmans and colleagues demonstrated increased baseline serum SP-D levels in patients with asthma, which further increased after allergen challenge (88). They showed significant correlations between serum SP-D levels and inflammatory parameters, such as ECP levels and eosinophil numbers in induced sputum. Unfortunately, they did not analyze sputum SP-D levels. Cheng demonstrated, howeverm in a small group of patients with asthma that SP-D levels in BALF were significantly increased versus control subjects (89), but that study not measure serum SP-D levels, so additional studies are necessary to calculate the BALF/serum ratio, which may be indicative for the degree of spill-over and a marker of disease severity.

Taken together, the SP-D data favor the possibility of a systemic spill-over in COPD and asthma. However, the mechanisms of how pulmonary SP-D enters the circulation are unclear, and several hypotheses exist (90), such as (1) alveolar-to-vascular leakage due to increased permeability of lung vessels (91), (2) efflux of SP-D directly from epithelial cells into the alveoli and alveolar vessels due to damaged integrity of epithelial secretory cells (92), (3) decreased clearance rate of SP-D from the circulation and (93), and (4) SP-D secretion by additional sources of SP-D like epithelial surfaces of nonpulmonary organs (94). Further studies are warranted to investigate these possibilities in COPD and asthma and to relate serum SP-D levels with local and systemic inflammatory changes.

Studies relating systemic inflammation to the level of local inflammation in patients with asthma are scarce. Serum levels of ECP correlate well with the number of activated eosinophils in bronchial biopsies of patients with asthma (67), but the source of serum ECP is likely circulating eosinophils, which continuously release ECP. Overall, the hypothesis that systemic inflammation in COPD and asthma is originated as a simple spill-over of the pulmonary compartment is not proven.

SYSTEMIC THERAPY ON LOCAL AND SYSTEMIC INFLAMMATION IN ASTHMA AND COPD: PROOF OF CONCEPT

The main therapy for asthma is treatment with inhaled corticosteroids, alone or in combination with long-acting β-agonists, resulting in reduction of a majority of symptoms. However, 5 to 10% of the population of persons with asthma has severe refractory disease and suffers from high morbidity. These patients are characterized by insensitivity to corticosteroids and have an altered inflammatory profile, marked by neutrophilic inflammation in the lungs and a shift toward a TH1-type immune response. The search for appropriate therapy for these patients is continuing. One candidate of interest is the cytokine TNF-{alpha}, which is known to mediate chronic inflammation in various immunologic diseases. Successful treatment by has been demonstrated for several diseases, such as Crohn's disease and rheumatoid arthritis (95, 96). Improvement of clinical parameters was associated with a reduction of the systemic inflammation (96).

Increased TNF-{alpha} has been detected in sputum, BALF, and bronchial biopsies of patients with asthma and in particular in patients with severe disease (97, 98). Patients with refractory asthma showed increased expression of membrane sTNF-{alpha}, TNF-R55, and TNF-{alpha}–converting enzyme on peripheral blood monocytes, indicating an up-regulation of the TNF-{alpha} axis (99). Administration of TNF-{alpha} to healthy subjects resulted in the development of airway hyperresponsiveness and neutrophilia (29). Blocking of TNF-{alpha} in murine models of asthma reduced antigen-induced airway inflammation and bronchial hyperreactivity (100), further supporting the role of TNF-{alpha} in asthma pathology.

A first intervention study revealed promising results. In an open label study, treatment of patients with severe asthma for 12 weeks with the soluble TNF-{alpha} receptor IgG1-Fc fusion protein etanercept resulted in improvement of asthma symptoms, lung function, and bronchial hyperresponsiveness (97) (Table 1). Although eosinophilic and neutrophilic numbers in sputum were reduced, this did not reach significance. In line with these data, Berry and colleagues demonstrated in a randomized, placebo-controlled study of refractory asthma an improvement of PC20, FEV1, and asthma-related quality of life (99). The observed enhanced expression of membrane TNF-{alpha} on peripheral blood monocytes was reduced due to etanercept treatment, and the improvement of clinical symptoms was related to the baseline expression of membrane-bound TNF-{alpha}. This suggests an important biological role for peripheral blood–bound TNF-{alpha} and deserves further attention. Although a reduction of sputum histamine was reported in this study, no effects of treatment on sputum differential cell count or ECP, IL-8, or cysteinyl leukotriene were detected. Based on this, the authors speculated that entanercept exerted its action through an effect on airway smooth muscle and mast cells. In a more recent study, the effect of etanercept on local and systemic inflammation in refractory asthma was further investigated (101). A reduction of macrophages was detected in sputum, whereas the inflammatory markers IL-6, IL-8, and IL-1β were not affected. TNF-{alpha} levels in serum increased strongly after treatment, which, as was postulated by the authors, could be due to binding of TNF-{alpha} to etanercept. In addition, albumin levels increased and circulating CRP levels decreased due to anti–TNF-{alpha} treatment, indicating that systemic inflammation is reduced with etanercept therapy in severe asthma.


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  		TABLE 1. EFFECT OF ANTI–TNF-{alpha} TREATMENT IN ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE

 
The effect of anti–TNF-{alpha} treatment has also been evaluated in mild asthma. Short-term treatment of patients with mild to moderate allergic asthma with etanercept did not attenuate pulmonary eosinophilia and was associated with an increase in epithelial lining fluid IL-4 level (102). Administration of infliximab, an anti–TNF-{alpha} antibody, in patients with moderate asthma revealed clinical improvement as demonstrated by reduced diurnal variation in peak expiratory flow rate and reduction of exacerbations. Moreover, a temporal reduction of sputum inflammatory markers such as IL-1{alpha}, IL-6, and human IFN-inducible protein was observed (103). In contrast, inflammatory cells in sputum or blood were not affected, and circulating levels of inflammatory markers were not evaluated in this study.

A new study analyzing the treatment effect of golimumab, a human monoclonal antibody against TNF-{alpha}, in severe persistent asthma reported an unfavorable risk benefit effect, which led to early discontinuation of study agent administration (104). Patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in treated patients. One death and all eight malignancies occurred in the active groups. Comparable health risks were observed in patients with rheumatoid arthritis (RA) treated with anti–TNF-{alpha} (105). This indicates that a delicate balance exists between benefit and risk of anti-TNF therapy and that careful evaluation is required.

Another important role of TNF-{alpha} in pathogenesis of COPD has been suggested, making it a valid candidate for this disease. Patients with COPD have elevated levels of TNF-{alpha} in sputum (8). In addition, TNF-{alpha} has been shown in animal models to induce pathological features associated with COPD, such as an inflammatory cell infiltrate into the lungs, pulmonary fibrosis, and emphysema (11, 106).

The first studies on the effects of infliximab in patients with COPD were reported by van der Vaart and colleagues (107). Patients with mild to moderate COPD did not show improvement on several clinical parameters, including FEV1 and quality-of-life indices, after treatment with infliximab. There was also no change in airway inflammation as measured by percentage of sputum neutrophils and levels of IL-6 and IL-8.

The effect of infliximab on local and systemic inflammation was further analyzed in a pilot study of 16 patients with COPD suffering from cachexia in a double-blind, placebo-controlled study (108). To monitor local inflammation, exhaled breath condensate was analyzed. Exhaled breath condensate levels of inflammatory markers were unchanged in patients receiving infliximab, indicating that local inflammation was not affected, in line with data from van der Vaart (107). In addition, systemic levels of acute-phase proteins (C-reactive protein, fibrinogen, and lipopolysaccharide-binding protein), IL-6, and sTNF-R55 had not changed. A small temporary increase in circulating levels of sTNFR75, myeloperoxidase, and Clara cell protein 16 were seen in treated patients, suggesting only a minor effect on systemic inflammation.

A multicenter, randomized, double-blind, placebo–controlled, parallel-group, dose-finding study in patients with moderate to severe COPD showed that infliximab had no treatment benefit for clinical parameters (109). Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-minute walk distance. However, an increased incidence of pneumonia and increased occurrences of pulmonary, head, and neck malignancies were observed in the treatment group. Altogether, these studies do not show an effect of infliximab on clinical or inflammatory markers and show elevated risk effect, excluding anti–TNF-{alpha} treatment as valuable therapy for COPD.

SYSTEMIC INFLAMMATION IN ASTHMA AND COPD: IS ADIPOSE TISSUE-MEDIATED INFLAMMATION THE CONNECTING LINK?

Until recently, the adipocyte was largely thought to be an inert storage cell whose main function was to store excess energy in the form of triglycerides. It is now apparent that adipocytes and adipose tissue produce a wide range of hormones and cytokines involved in glucose metabolism, lipid metabolism, coagulation, inflammation, blood pressure regulation, and feeding behavior (110). These plasma adipocytokine levels rise with an increase in adipocyte tissue and adipocyte volume, except for plasma adiponectin, which is lower in obesity (111, 112). Leptin, the first adipocyte hormone identified, influences food intake through a direct effect on the hypothalamus (113, 114) but also has profound effects on the immune system. The known actions of leptin on immune responses have been extensively reviewed (115) and include modulation of monocytes/macrophages, neutrophils, basophils, eosinophils, and natural killer and dendritic cells. Leptin modifies T-cell balance, induces T-cell activation, and changes the pattern of T-cell cytokine production toward a TH1 response, accounting for a proinflammatory role of leptin in several inflammatory conditions (115). A remarkable aspect of the effects of leptin on the immune system is its action as a proinflammatory cytokine. Leptin mRNA and circulating leptin levels are increased by a number of inflammatory stimuli, including IL-1, IL-6, and lipopolysaccharide (116). The role of leptin in the pathophysiology of systemic inflammation and systemic disease manifestations in asthma and COPD is still unexplored. Limited studies have related leptin metabolism to metabolic state in patients with COPD (63, 117, 118). Particularly the involvement of leptin in the local and systemic inflammatory response is intriguing.

Leptin is present in induced sputum samples of patients with COPD and showed a very strong correlation with sputum TNF-{alpha} and CRP (119). Because leptin levels were tenfold higher in plasma versus sputum, it may be possible that leptin measured in sputum is mainly derived from the circulation. On the other hand, Vernooy and colleagues recently demonstrated that expressing bronchial epithelial cells, type II pneumocytes, and macrophages, among others, are a significant source of leptin in peripheral lung tissue of patients with COPD (120). Leptin-expressing bronchial epithelial cells and alveolar macrophages were markedly higher in patients with severe COPD and in exsmokers than in never smokers. In addition, exposure of cultured primary bronchial epithelial cells to smoke resulted in a dose-dependent increased leptin mRNA expression and protein production. The fact that normal lung tissue displays particularly high levels of leptin receptors, including its functional form Ob-Rb (121), designates the lung as a peripheral site of action for leptin in pulmonary diseases. Leptin was recently shown to stimulate intracellular signal transduction in bronchial epithelial cells (120). The functional role of leptin in the pulmonary compartment is under investigation. Mancuso and colleagues showed that leptin is a key mediator in host defense against airborne pathogens (122, 123) and augments the functional capacity of infiltrated inflammatory cells (124, 125). In a smoking mouse model, leptin was found to modulate the recruitment of neutrophils, dendritic cells, and T cells (126). In mice exposed to asthma triggers (e.g., ozone [127] and ovalbumin [128]), deficiency in leptin signaling was shown to augment airway hyperresponsiveness, accompanied by reduced airway inflammation.

Adiponectin was discovered almost at the same time as leptin. Adiponectin has an array of antiatherosclerotic effects and exerts relevant actions on innate and adaptive immunity. It interferes with macrophage function by inhibiting phagocytic activity and IL-6 and TNF production. Adiponectin reduces B-cell lymphopoiesis, decreases T-cell response, and induces the production of important antiinflammatory factors such as IL-10 and IL1-RA by human monocytes, macrophages, and dendritic cells (129). This protective antiinflammatory function of adiponectin in asthma and COPD needs further exploration.

IL-6 can be produced in large quantities by abdominal adipose tissue and is a well-known proinflammatory cytokine. Various other adipocytokines are produced by adipocytes, such as resistin, visfatin, omentin, and retinol-binding protein 4, which metabolic and inflammatory properties are topic of current investigations.

This concept of adipocyte dysfunction may provide a pathophysiological framework for understanding systemic inflammatory processes in some patients with asthma and COPD and of understanding the clustering of comorbidities in some patients suffering from chronic respiratory diseases.

CONCLUSIONS

The presence of low-grade systemic inflammation is generally believed to be a key pathogenetic mechanism underlying most of the systemic manifestations of airways disease and COPD in particlar. However, many questions related to systemic inflammation in COPD and in asthma remain unanswered, such as its prevalence and relationship with other components of the disease. Systemic inflammation is defined by assessment of a particular inflammatory marker. The relationship between these individual markers is poorly explored, and the possibility of a combined inflammatory index needs to be evaluated in longitudinal studies. The origin of systemic inflammation remains unclear. The spill-over theory is probably an oversimplification of the complexity of these systemic alterations and does not fit with the absence of systemic inflammation in a large group of patients with COPD and probably a majority of patients with asthma. Body compositional changes and particularly adipocyte dysfunction need to be considered as a new mechanistic links to understand systemic inflammatory changes. Further knowledge of the underpinnings of adipocyte function dysfunction in these obstructive disease processes may provide new targets for intervention and management.

FOOTNOTES

Supported by a Veni grant from the Netherlands Organization of Scientific Research (N.L.R), by an unrestricted grant from GSK Europe – European COPD Centre of Excellence (N.L.R., M.A.D.), and by an unrestricted grant from the De Weijerhorst Foundation (J.H.J.V.).

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 22, 2009; accepted in final form October 20, 2009)

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