The overall goals of this proposal are to understand the cellular and molecular mechanisms that govern lung tissue injury and repair. To accomplish this goal, two different cell lineages (alveolar epithelium and fibroblasts) will serve as models of developmentally regulated and injury induced changes in specific genes, the products of which play a role in inflammation and tissue repair. To accomplish these goals, we will: a) ascertain the pattern and mechanisms of change in complement gene expression during differentiation of embryonic lung cells to alveolar and b) elucidate the mechanisms of cytokine and growth factor regulation/counter-regulation of complement gene expression in fibroblasts. The complement genes (C2, factor B, C3, C4) provide a useful window into the developmental and tissue injury dependent process because they are expressed in both cell lineages, developmental and cytokine induced regulation, and growth factor counter-regulation have already been recognized, and these complement proteins play a role in host defenses against infection. Cellular and molecular biological methods will be utilized to address these questions. The proposed studies offer the promise of understanding pulmonary tissue injury, inflammation and repair to allow development of systematic approaches to a variety of pulmonary disorders as diverse as bronchopulmonary dysplasia and bronchiolitis obliterans, among others.
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