CAPTOPRIL INHIBITS APOPTOSIS IN HUMAN LUNG EPITHELIAL-CELLS - A POTENTIAL ANTIFIBROTIC MECHANISM

The angiotensin-converting enzyme inhibitor captopril has been shown t o inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reas ons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate t he Fas receptor induced epithelial cell apoptosis as detected by chrom atin condensation, nuclear fragmentation, DNA fragmentation, and incre ased activities of caspase-1 and -3. Apoptosis was not induced by isot ype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antib odies, 50 ng/ml of captopril completely abrogated apoptotic indexes ba sed on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhi bition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of ca ptopril on pulmonary fibrosis may be related to prevention of lung epi thelial cell apoptosis.