The Role of Gelatinase B in Terminal Airway Remodeling

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DESCRIPTION (provided by applicant): The terminal airways are sites of abnormal structure and function in a number of chronic lung disorders, most notably COPD, yet relatively little is known about the cell and molecular biology of the epithelial cells lining terminal airways. Recent observations indicate an important role of the matrix metalloproteinase gelatinase B (MMP-9; gel B) in the function of terminal airway epithelium. Gel B-deficient ("knockout") mice do not show the alveolar bronchiolization seen in wild type mice after exposure to bleomycin, nor do they show the normal rapid repair of terminal airway epithelium after exposure to napthalene, an agent that causes necrosis of the Clara cells lining the terminal airways. The regulation of gel B expression in terminal airway epithelium is not well understood. Recent studies have shown that extracellular matrix metalloproteinase inducer, EMMPRIN, is prominent in alveolar and terminal airway epithelium in human pulmonary fibrosis and after intratracheal bleomycin in mice. The studies proposed will examine: (1) whether gel B expression by Clara cells can rescue the defects in alveolar bronchiolization after bleomycin and epithelial repair after napthalene in gel B "knockout" mice; (2) the migratory properties of Clara cells and the relationship of gel B to Clara cell migration; and (3) the effects of EMMPRIN on the expression of matrix metalloproteinases, especially gel B, by lung cells and the intact lung. To assess the role of Clara cell gel B on alveolar bronchiolization after bleomycin and terminal airway repair after napthalene, transgenic mice will be generated on the gel B knockout background which will express gel B in Clara cells in a tetracycline-inducible manner. To study the migration of Clara cells and the role of gel B, Clara cells will be isolated from gel B-deficient and wild type mice and their migration quantified in response to various chemotactic factors and in relation to contact with various extracellular matrix components. To determine whether EMMPRIN affects expression of gel B and other matrix metalloproteinases, various types of lung cells, including Clara cells, will be exposed to recombinant EMMPRIN and evaluated for matrix metalloproteinase expression. Taken together, the studies proposed will contribute to better understanding of the biology of terminal airway epithelium, a site that is central in many chronic lung disorders, especially COPD.