We examined the association between 25 different plasma markers of inflammation and two physiologic parameters of COPD in a well-defined clinical population. The main observation was that increasing severity of airflow limitation, as defined by the % FEV1, was associated with increasing systemic concentrations of IL-13, and the inflammatory chemokines CCL2/MCP-1, CCL4/MIP-1β, and CCL11/eotaxin after adjusting for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use. Furthermore, increasing severity of diffusion impairment, as defined by the % DLCO, was associated with increasing IL-13, CXCL9/Mig, and G-CSF concentrations and decreasing soluble Fas concentrations.
In both univariate and multivariate analysis, increasing plasma concentration of the T helper 2 (TH2) type cytokine IL-13 was associated with increasing severity of airflow obstruction, suggesting that IL-13 may be an important mediator in human COPD. The association between increasing IL-13 concentrations and increasing severity of airflow obstruction could not be accounted for by a subset of the cohort with bronchodilator reversibility. This finding suggests that the association is unlikely due to misclassification of asthmatic patients in our COPD cohort.
IL-13 is implicated in airway mucin production and airway inflammation [45
]. IL-13 has been previously shown to induce mucous metaplasia and chemokine expression in animal models of allergic airway inflammation and emphysema [47
]. Others have recently shown that both CD4+
T cells in the bronchoalveolar lavage fluid of COPD patients expressed significantly higher percentages of IL-13 than smokers with normal lung function and never smokers [28
]. Similar to our findings, these authors showed a negative correlation between intracellular IL-13 and % FEV1
Three of seven chemokines tested were associated with increasing severity of airflow obstruction: CCL2/MCP-1, CCL4/MIP-1β, and CCL11/Eotaxin. In addition, CXCL9/Mig was associated with increasing severity of diffusion impairment. These chemokines recruit primarily monocytes, T lymphocytes, and eosinophils, inviting the possibility that soluble proteins that promote inflammatory cell recruitment contribute to the low-grade systemic inflammation observed in COPD. CCL2/MCP-1 recruits monocytes and T lymphocytes expressing the receptor CCR2 [49
], and increased concentrations of this chemokine have been reported in induced sputum, BAL and lung tissue of COPD individuals [38
]. CCL4/MIP-1β can recruit CCR5 expressing monocytes and T lymphocytes [49
]. Our data corroborates findings showing a negative correlation between CCL4/MIP-1β concentrations in the BAL from patients with chronic bronchitis and the % FEV1
]. CCL11/Eotaxin is involved in eosinophil recruitment [51
], and CCL11/eotaxin concentrations are increased in the sputum of patients with exacerbations of chronic bronchitis [23
]. However, some COPD patients with stable disease also show airway eosinophilic inflammation [52
A secondary goal of this study was to explore whether systemic cytokines are associated with severity of diffusion impairment, the physiologic parameter that corresponds best to the loss of alveolar-capillary bed surface area in emphysema. In the smaller cohort that received DLCO measurements, it is interesting that CXCL9/Mig concentration was inversely associated with % DLCO. CXCL9/Mig recruits CXCR3 expressing T lymphocytes [49
]. Saetta and colleagues have previously shown increased numbers of CXCR3 expressing T lymphocytes in peripheral airways of COPD patients [53
]. Upon stimulation with CXCL9/Mig, CD14+
macrophages of human emphysematous lungs can increase metalloproteinase production in vitro [26
]. Thus, recent findings suggest a potential link between this chemokine and the pro-elastolytic environment of emphysema.
Increasing concentrations of plasma G-CSF are also associated with increasing severity of diffusion impairment. G-CSF is involved in neutrophil mobilization and survival [54
], however its role in COPD is not yet known. There are increased numbers of granulocytes in the sputum and BAL [38
] in addition to small airways [55
] of COPD patients, leading others to speculate that granulocyte survival in the lungs may be enhanced in COPD by mediators such as G-CSF [38
Another molecule identified is soluble Fas. Decreasing concentrations of soluble Fas are associated with increasing severity of diffusion impairment. Soluble Fas, a result of alternative mRNA splicing, inhibits apoptosis by competitively binding FasL and preventing its interaction with the membrane bound Fas receptor [56
]. The relationship between systemic levels of soluble Fas and COPD is unclear, as other smaller studies have shown variable findings of either elevation or no difference compared with controls [17
]. Our results suggests that a systemic imbalance of the anti-apoptotic factor soluble Fas occurs in the setting of a pro-apoptotic environment of the lungs in COPD.
The limitations of this present study include the size of the cohort and its cross-sectional nature. The modest size, particularly the number of subjects with milder lung function impairment (GOLD 0–1 stages), may limit the ability to detect significant associations between systemic markers and lung function impairment. Furthermore, we included age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use in the multivariate model. It is uncertain whether adjustment for these covariates is appropriate. Thus, we present both univariate and multivariate analysis. We also recognize that the observed associations between plasma concentrations of a protein and lung function severity do not necessarily invoke a cause-effect relationship. However, the findings of this study can serve as the basis for a larger prospective cohort study examining a narrower profile of cytokines on a longitudinal basis.