Abstract
BackgroundCigarette 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 FindingsThe objective of this study was to assess IL-1 α and β 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-1α and β. Here, we demonstrate an underappreciated role for IL-1α expression in COPD. While a strong correlation existed between IL-1α and β levels in patients during stable disease and periods of exacerbation, neutrophilic inflammation was shown to be IL-1α-dependent, and IL-1β- and caspase-1-independent in a murine model of cigarette smoke exposure. As IL-1α 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-1α+ hematopoietic cells and the IL-1R1+ epithelial cells regulates smoke-induced inflammation. IL-1α/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 SignificanceThis study provides compelling evidence that IL-1α is central to the initiation of smoke-induced neutrophilic inflammation and suggests that IL-1α/IL-1R1 targeted therapies may be relevant for limiting inflammation and exacerbations in COPD.
Highlights
The adverse effect of cigarette smoking on human health is well established [1,2]
This study provides compelling evidence that IL-1a is central to the initiation of smokeinduced neutrophilic inflammation and suggests that IL-1a/IL-1 receptor type 1 (IL-1R1) targeted therapies may be relevant for limiting inflammation and exacerbations in chronic obstructive pulmonary disease (COPD)
IL-1a is increased in COPD patients and correlates with increased IL-1b levels
Summary
Cigarette smoking is a main risk factor for lung cancer and directly correlates with the development of chronic obstructive pulmonary disease (COPD). While aberrant immune-inflammatory responses are likely key for driving increased inflammation observed in COPD patients during stable disease and episodes of acute exacerbations, the precise cellular and molecular mechanisms remain to be elucidated. To-date, no studies in humans or mice have examined expression and function of IL-1a in inflammatory processes associated with cigarette smoke exposure and inflammatory exacerbation of stable COPD, despite the multiple roles the IL-1 family members have been shown to play in a multitude of inflammatory conditions (reviewed in [13]). Cigarette smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. The cellular and molecular mechanisms that contribute to COPD pathogenesis are still poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
