INTEGRIN AVB6--ROLE IN BRONCHIOLAR INJURY/REPAIR

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The terminal bronchiolar epithelium is a primary target of injury for many metabolically activated xenobiotics. Little is known about bronchiolar repair following such acute injury, but it is known that a failure to repair results in chronic bronchiolitis, bronchiolitis obliterans or neoplasia. Many aspects of the repair process are medicated by integrins: heterodimeric, transmembrane glycoproteins involve in cell-cell or cell-matrix adhesion. A novel monogamous, non- constitutive alpha v beta 6 integrin, has been identified within the epithelia of branching airways of developing lung and is upregulated in alveoli and bronchi during inflammation. Previous studies of acute injury suggest that the alpha v beta 6 integrin plays a critical role in repair, especially in cell proliferation. Using a well defined model of bronchiole epithelial injury injury in mice, naphthalene will be used to experimentally induce acute injury to examine the following specific aims: 1)Establish the dose of naphthalene that induces the same degree of Clara cell cytotoxicity in both wild type adult and 7 day old mice and beta 6 transgenic knockout mice, 2)Define the pattern of expression of the alpha v beta 6 integrin during bronchiolar epithelial repair following acute Clara cell toxicity in adult and neonatal wild type mice, and 3) Compare the pattern of repair in adult wild type mice with beta 6 knockout mice.