Captopril inhibits proliferation of human lung fibroblasts in culture: a potential antifibrotic mechanism.
The angiotensin converting enzyme (ACE) inhibitor captopril, a free-thiol compound used widely as an antihypertensive agent, also inhibits radiation-induced pulmonary fibrosis in rats (Ward et al., Int J Radiat Oncol Biol Phys 19:1405, 1990). In an attempt to clarify the antifibrotic mechanism of captopril in vivo, the present study examined the effect of the drug on proliferation of human lung fibroblasts in culture. Captopril produced a drug dose-dependent reduction in fibroblast proliferation and 3H-thymidine incorporation during a 24-72-hr incubation. This cytostatic action of captopril was not the result of cytotoxicity as assessed by trypan blue exclusion, or by 51Cr or lactate dehydrogenase (LDH) release. Fibroblasts stimulated to proliferate by basic FGF were more sensitive to the antimitotic effect of captopril than were unstimulated cells. The ability of captopril to inhibit 3H-thymidine incorporation was not reversed by exogenous angiotensin 2, and was not mimicked by the nonthiol ACE inhibitor lisinopril. These data indicate 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 3H-thymidine incorporation, indicating that the antimitotic action of captopril may represent a nonspecific sulfhydryl effect. This study suggests that the antifibrotic activity of captopril in irradiated lung may result in part from a direct inhibition of fibroblast proliferation, particularly in fibroblasts responding to mitogenic stimuli.
Nguyen
L
L
Department of Radiology, Northwestern University Medical School, Chicago, Illinois 60611.
Ward
W F
WF
Ts'ao
C H
CH
Molteni
A
A
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008168:Lung / Q000166:cytology*; D008938:Mitosis / Q000187:drug effects; D010396:Penicillamine / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000517:prevention & control; D051381:Rats; D013936:Thymidine / Q000378:metabolism
D016222:Fibroblast Growth Factor 2; D000804:Angiotensin II; D004247:DNA; D002216:Captopril; D007770:L-Lactate Dehydrogenase; D010396:Penicillamine; D013936:Thymidine