Approximately 150,000 people in the United States develop acute lung injury (All) and the acute respiratory distress syndrome (ARDS) annually (1). Despite research driven advances in therapy, ~40% of these patients will die. All and ARDS often manifest as a part of a systemic inflammatory process resulting in the development of diffuse alveolar epithelial damage and capillary injury with the exudation of protein rich fluid into the alveolar space. As part of the alveolar-capillary repair ALI/ARDS patients develop a fibroproliferative process that is characterized by the proliferation of mesenchymal cells, differentiation of mesenchymal cells into myofibroblasts and deposition of extracellular matrix. The molecular and cellular mechanisms underlying fibroproliferation during ALI and ARDS are not fully understood. Transforming growth factor-beta 1 (TGF-31) is integral for fibroblast activation and tissue repair. Multiple reports over the last 10 years have described a role for early fibroblast activation in determining the outcome of patients with the ARDS. How TGF-31 induces lung fibrosis following epithelial injury is not fully understood. To date there is no genetic evidence to indicate whether epithelial apoptosis is sufficient and required for the initiation of lung injury followed by pulmonary fibrosis. We propose that TGF-31 induces lung injury and fibrosis by activating the intrinsic apoptotic pathway in alveolar epithelial cells. The intrinsic apoptotic pathway is regulated by the Bcl-2 family members. In support of our hypothesis, we have reported that loss of the proapoptotic Bcl-2 family member Bid prevents TGF-31 induced fibrosis in mice. The purpose of this grant is to elucidate the mechanisms by which TGF-31 induces Bid dependent epithelial cell death resulting in lung injury and fibrosis. The current proposal will address these questions utilizing genetics in mouse models of lung injury and fibrosis.
From a clinical perspective, mortality in ARDS is unacceptably high despite improved supportive care and ventilatory strategies. In vitro, animal and human data implicate TGF-31 action on alveolar epithelial cells as of primary importance in alveolar injury and repair. Our study has the potential to determine the role of TGF- 31 signaling pathway in epithelial apoptosis that may provide the rationale for the development of novel therapeutic strategies.
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