Clara Cells, Their Secretions in Lung Immuno-regulation

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DESCRIPTION (provided by applicant): Even though cytokine production by cells of the immune system can significantly impact epithelial cell function, little is known of reciprocal roles for epithelial cells in regulation of the immune system. This is a significant issue when trying to understand the complex series of events that lead to deteriorating lung function among individuals with chronic inflammatory and/or immunological lung diseases such as COPD and asthma. There is a growing recognition that the conducting airway epithelium is dynamic in its function and that chronic lung disease results in predictable changes to epithelial cells. Among these changes are alterations in nonciliated airway epithelial cell function, for which reduced abundance of Clara cell secretory protein (CCSP) serves as a biomarker. Whether changes to Clara cells are a cause or a nonciliated airway epithelial cells contribute to exacerbation of lung disease and a continuing decline in lung function. Our recent studies in CCSP null mice (CCSP-/-) demonstrate that Clara cells fulfill important roles in defense against environmental agents in addition to serving critical immunoregulatory functions. Central to this proposal is the observation that CCSP-/- mice have elevated local production of IgA. Moreover, expression of IgA is dramatically up regulated following in vivo endotoxin exposure of CCSP-/- but not wild type mice, demonstrating fundamental differences in B-cell responsiveness with CCSP deficiency. We hypothesize that CCSP functions to suppress the immune system through either directly or indirectly regulating local B-cell function, and that these changes in B-cell function impact innate mucosal defense. If correct, changes in Clara cell function may lead to hyperstimulation of the local immune response which, although beneficial with respect to the acute clearance of colonizing microorganisms, could exacerbate airway disease and dysfunction. Aims will address four specific aspects of altered lung function that accompanies CCSP deficiency: 1) does CCSP deficiency result in altered innate and/or adaptive immunity, 2) are changes in lung immunoregulation and innate defense directly related to loss of CCSP, 3) are differences in innate defense with CCSP deficiency directly related to altered B-and/or T-cell function, and 4) which cell types are most sensitive to CCSP-dependent alterations in endotoxin signaling. By addressing these aims we will define mechanisms by which CCSP deficiency leads to altered immunoregulation within the lung. This knowledge may help in the development of strategies to block inappropriate immunological responses that lead to deteriorating lung function among individuals with chronic lung disease.