Mechanisms driving airway inflammation in chronic lung disease

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DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a major source of morbidity and mortality in the Veteran population. Although cigarette smoking is the major risk factor, determinants of COPD development and progression remain incompletely understood. In this application, we propose to test a novel theory of COPD pathogenesis that we developed based on striking correlations between altered mucosal immunity in small airways and key parameters of COPD, including airway wall thickening, inflammatory cell influx, and airflow limitation. Secretory IgA (SIgA), the most abundant immunoglobulin in the airways, is delivered to the surface of small airways by the polymeric immunoglobulin receptor (pIgR), which is expressed on the basolateral surface of airway epithelial cells. In the setting of epithelial remodeling, which is pervasive in COPD, our preliminary data indicate that epithelial cells down-regulate pIgR expression and are no longer able to maintain a normal mucosal immune barrier. Exposure of mice to mainstream cigarette smoke down-regulates pIgR expression and reduces SIgA levels in the airways prior to development of COPD-like pathology. In pIgR deficient (pIgR-/-) mice, which lack SIgA in their airways, lungs are normal at birth and young adulthood but spontaneously develop COPD-like airway and parenchymal remodeling by 6 months of age. These structural changes are worsened by exposure to cigarette smoke and are associated with bacterial invasion of the airway epithelial layer, epithelial NF-kB activation, and influx/activation of leukocytes, similar o findings in humans with COPD. These data suggest that SIgA on the airway surface plays an essential role in defending the airway from environmental challenges and that altered mucosal immunity contributes to development and progression of COPD. Therefore, we hypothesize that in COPD a dysfunctional mucosal immune barrier with reduced SIgA on the surface of small airways allows access of microorganisms and airborne antigens to the airway epithelium. As a result, persistent/recurrent NF-�B activation in the epithelium drives expression of pro- inflammatory mediators that recruit and activate leukocytes. Accumulation of activated leukocytes (particularly macrophages) in the distal airways and lung parenchyma perpetuates the inflammatory state in COPD and leads to small airway remodeling and emphysema. To test this hypothesis, we propose the following specific aims: 1) to identify mechanisms that drive small airway remodeling and emphysema in mice with disrupted mucosal immune barrier function in the lungs, 2) to determine whether altering the bacterial burden in lungs of pIgR deficient mice alters development and progression of COPD-like pathology, and 3) to define the impact of NF-kB activation and macrophage recruitment/activation on development of COPD-like pathology in pIgR deficient mice. By defining the contribution of altered mucosal immunity to COPD, proposed studies will result in improved understanding of COPD pathogenesis and hopefully will lead to new effective therapies.