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Abstract

Background: Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. Despite this, the cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood.

Methodology and Principal Findings: The objective of this study was to assess IL-1alpha and beta expression in COPD patients and to investigate their respective roles in perpetuating cigarette smoke-induced inflammation. Functional studies were pursued in smoke-exposed mice using gene-deficient animals, as well as blocking antibodies for IL-1alpha and beta. Here, we demonstrate an underappreciated role for IL-1alpha expression in COPD. While a strong correlation existed between IL-1alpha and beta levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1alpha-dependent, and IL-1beta- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1alpha was predominantly expressed by hematopoietic cells in COPD patients and in mice exposed to cigarette smoke, studies pursued in bone marrow chimeric mice demonstrated that the crosstalk between IL-1alpha+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1alpha/IL-1R1-dependent activation of the airway epithelium also led to exacerbated inflammatory responses in H1N1 influenza virus infected smoke-exposed mice, a previously reported model of COPD exacerbation.

Conclusions and Significance: This study provides compelling evidence that IL-1alpha is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1alpha/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.