The airway epithelium has a major role in maintaining airway homeostasis and may be damaged extensively in inflammatory diseases such as asthma. Environmental exposure to allergen may worsen asthma in part by causing epithelial cell shedding and cell death. Although denudation of bronchial epithelium is a cardinal feature of the pathology of asthma, the mechanisms underlying this phenomenon remain unknown. As part of their potent inflammatory effects in airways, corticosteroids induce apoptosis in migratory eosinophils and T-lymphocytes. New data from our laboratory suggest that corticosteroids can also induce apoptosis in airway epithelium, both in cultured cells and in animal models. As such, corticosteroids may possess a heretofore unrecognized adverse consequence: induction of epithelial cell apoptosis and prolongation of bronchial epithelial denudation. Continued epithelial damage may lead to the development of sub- epithelial fibrosis and chronic airway remodeling. The central hypothesis of our proposal is that corticosteroid treatment is deleterious to bronchial epithelial survival, even though it promotes resolution of airway inflammation. Our goal is to answer two specific hypotheses: 1) whether corticosteroids elicit epithelial cell apoptosis, and worsen epithelial cell apoptosis during allergen challenge; and 2) whether differentiation factors for epithelial cells counter corticosteroid-induced apoptosis. Specific assays to determine apoptosis both in culture and in airway and lung tissue sections will be used. Signaling mechanisms for initiation of apoptosis by corticosteroids will be examined by Western blot, fluorescent assays, and RT-PCR. The use of transfected human airway epithelial cells will determine whether differentiation factors, such as transforming growth factor-beta and cis-retinoic acid, attenuate apoptosis and speed repair. A mouse model will be used to demonstrate the effect of corticosteroid and differentiation factor treatment on epithelial cell apoptosis, repair and integrity in vivo. This model will help determine the interplay between airway inflammation and corticosteroid treatment on the genesis of epithelial damage. These experiments will demonstrate mechanisms by which epithelial cell apoptosis leads to impaired repair of the airway mucosa after injury. Demonstration that corticosteroids worsen epithelial cell apoptosis, shedding and death would suggest that at least one of the pathologic findings in chronic asthma may be a result of treatment for the disease. These data would help lead to new therapeutic ideas and modalities in the treatment of asthma to suppress inflammation while preventing mucosal damage.

R01HL063300

1999-09-01

2004-08-31