The long-term goal of the applicant is to elucidate the control of alveolar epithelial repair after lung injury and its anomalies that lead to lung disease. Recent evidence suggests that apoptosis of alveolar epithelial cells (AEC) is a key determinant in both the initiation and outcome of fibrotic lesions. In support of that hypothesis, the applicant has shown that the angiotensin converting enzyme inhibitor captopril, which was shown earlier to block the pathogenesis of experimental lung fibrosis (IPF), also potently inhibits apoptosis of AEC but not the lung fibroblast apoptosis required for the resolution of fibrotic lesions. Preliminary data identified a peptide inhibitor of Caspase 3 (DEVD-fmk) which, like captopril, also provides specific inhibition of apoptosis in AEC but not in lung fibroblasts.
In Specific Aim 1, an established rat model which closely mimics human IPF will be used to determine if specific inhibition of AEC apoptosis by DEVD-fmk can block the initiation of IPF as does captopril.
In Aim 2, both compounds will be tested for the ability to """"""""rescue"""""""" experimental animals already symptomatic with advanced IPF, a situation which is encountered clinically but seldom examined in animal models.
Specific Aims 3 and 4 will define the regulation of AEC apoptosis by the local renin-angiotensin system, a regulatory mechanism previously unknown to be active in these cells, and Aim 5 will determine the physiological significance of this system in an animal model and in diseased human lung. These studies will test the hypothesis that AEC apoptosis is a critical step in the pathogenesis of IPF, and will begin to identify targets and new therapeutic strategies for the manipulation of AEC apoptosis in fibrotic lung disease.
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