Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine.
The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.
Molteni
A
A
Ward
W F
WF
Ts'ao
C H
CH
Solliday
N H
NH
Dunne
M
M
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use*; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000032:analysis / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D016686:Monocrotaline; D009929:Organ Size / Q000187:drug effects; D010396:Penicillamine / Q000627:therapeutic use*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010947:Plants, Toxic; D011392:Proline / Q000031:analogs & derivatives*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D011763:Pyrrolizidine Alkaloids; D051381:Rats; D011919:Rats, Inbred Strains; D012674:Senecio
D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D011392:Proline; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D010396:Penicillamine; D006909:Hydroxyproline