Inverse association of plasma IL-13 and inflammatory chemokines with lung function impairment in stable COPD: a cross-sectional cohort study

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome characterized by varying degrees of airflow limitation and diffusion impairment. There is increasing evidence to suggest that COPD is also characterized by systemic inflammation. The primary goal of this study was to identify soluble proteins in plasma that associate with the severity of airflow limitation in a COPD cohort with stable disease. A secondary goal was to assess whether unique markers associate with diffusion impairment, based on diffusion capacity of carbon monoxide (DLCO), independent of the forced expiratory volume in 1 second (FEV1).

Methods: A cross sectional study of 73 COPD subjects was performed in order to examine the association of 25 different plasma proteins with the severity of lung function impairment, as defined by the baseline measurements of the % predicted FEV1 and the % predicted DLCO. Plasma protein concentrations were assayed using multiplexed immunobead-based cytokine profiling. Associations between lung function and protein concentrations were adjusted for age, gender, pack years smoking history, current smoking, inhaled corticosteroid use, systemic corticosteroid use and statin use.

Results: Plasma concentrations of CCL2/monocyte chemoattractant protein-1 (CCL2/MCP-1), CCL4/macrophage inflammatory protein-1 beta (CCL4/MIP-1 beta), CCL11/eotaxin, and interleukin-13 (IL-13) were inversely associated with the % FEV1. Plasma concentrations of soluble Fas were associated with the % DLCO, whereas CXCL9/monokine induced by interferon-gamma (CXCL9/Mig), granulocyte- colony stimulating factor (G-CSF) and IL-13 showed inverse relationships with the % DLCO.

Conclusion: Systemic inflammation in a COPD cohort is characterized by cytokines implicated in inflammatory cell recruitment and airway remodeling. Plasma concentrations of IL-13 and chemoattractants for monocytes, T lymphocytes, and eosinophils show associations with increasing severity of disease. Soluble Fas, G-CSF and CXCL9/Mig may be unique markers that associate with disease characterized by disproportionate abnormalities in DLCO independent of the FEV1.

Figure 1

The relationship between natural log (LN) IL-13 concentrations in pg/mL and % predicted FEV1. The line was calculated using conditional standardization of the regression results for a patient with mean and modal values for the covariates in the model. The standardized line thus represents the relationship between IL-13 and FEV₁ for a man, age 63, who does not currently smoke, with mean pack year smoking history of 52.5 years, who is not on statins or systemic steroids, but is on inhaled steroids (β = -0.01).

Figure 2

The relationship between natural log (LN) IL-13 concentrations in pg/mL and % predicted DLCO. The line was calculated using conditional standardization of the regression results for a patient with mean and modal values for the covariates in the model. The standardized line thus represents the relationship between IL-13 and DLCO for a man, age 63, with a FEV₁ of 51 % predicted, who does not currently smoke, with mean pack year smoking history of 52.5 years, who is not on statins or systemic steroids, but is on inhaled steroids (β = -0.02).