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 mgfkgfday, p.0.; ( 3 ) Dpenicillamine, 30 mg/kg/day, p.0.; (4) monocrotaline, 2.4 mg/kg/day, p.0.; (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 monocrotalinetreated rat lung. 0 1985 Society for Expenmental Blology and Medicine.

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Abstrucf.To study the role of endothelial damage in the pathogenesis of lung injury induced by the pyrrolizidine alkaloid monocrotaline, three functions (angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI,) production) associated with the pulmonary endothelium were examined, and were correlated with pulmonary arterial perfusion and ultrastructure in rats receiving monocrotaline in their drinking water (20 mg/liter) for 1-12 weeks. Lung ACE activity increased after 1 week of monocrotaline, then decreased steadily from 1 to 6 weeks, before plateauing at approximately 55% of normal. PLA activity in monocrotaline-treated lungs did not change significantly for the first 2 weeks, then decreased to 59 and 79% of the control value after 6 and 12 weeks, respectively. In contrast, PGI, production increased progressively, reaching 140 and 270% of the control level after 6 and 12 weeks of monocrotaline treatment, respectively. These endothelial functional changes were not accompanied by significant changes in pulmonary arterial perfusion as visualized by 9 9 m T~ lung scans. Electron microscopy of monocrotaline-treated lungs revealed endothelial damage (perivascular and subendothelial edema, degeneration) starting at 1 week, and inflammatory and hemorrhagic reactions starting at 2 weeks. At 6 and 12 weeks, monocrotaline-treated rats also exhibited increased pulmonary arterial wall thickness, right heart enlargement, and cardio-and hepatomegaly. Thus, monocrotaline-induced pulmonary injury is accompanied, and in some cases preceded, by structural and functional abnormalities in the pulmonary endothelium. 88