CAPTOPRIL INHIBITS PROLIFERATION OF HUMAN LUNG FIBROBLASTS IN CULTURE- A POTENTIAL ANTIFIBROTIC MECHANISM

The angiotensin converting enzyme (ACE) inhibitor captopril, a free-th iol compound used widely as an antihypertensive agent, also inhibits r adiation-induced pulmonary fibrosis in rats (Ward et al., Int J Radiat Oncol Biol Phys 19:1405, 1990). In an attempt to clarify the antifibr otic mechanism of captopril in vivo, the present study examined the ef fect of the drug on proliferation of human lung fibroblasts in culture . Captopril produced a drug dose-dependent reduction in fibroblast pro liferation and H-3-thymidine incorporation during a 24-72-hr incubatio n. This cytostatic action of captopril was not the result of cytotoxic ity as assessed by trypan blue exclusion, or by Cr-51 or lactate dehyd rogenase (LDH) release. Fibroblasts stimulated to proliferate by basic FGF were more sensitive to the antimitotic effect of captopril than w ere unstimulated cells. The ability of captopril to inhibit H-3-thymid ine incorporation was not reversed by exogenous angiotensin 2, and was not mimicked by the nonthiol ACE inhibitor lisinopril. These data ind icate that the cytostatic effect of captopril was not attributable to ACE inhibition. Penicillamine, a thiol compound with virtually no ACE inhibitory activity, also reduced fibroblast H-3-thymidine incorporati on, indicating that the antimitotic action of captopril may represent a nonspecific sulfhydryl effect. This study suggests that the antifibr otic activity of captopril in irradiated lung may result in part from a direct inhibition of fibroblast proliferation, particularly in fibro blasts responding to mitogenic stimuli.