Monocrotaline-induced cardiopulmonary injury in rats. Modification by the neutrophil elastase inhibitor SC39026.
Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.
Molteni
A
A
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611.
Ward
W F
WF
Ts'ao
C H
CH
Hinz
J M
JM
D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D002723:Chlorobenzoates / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis; D006909:Hydroxyproline / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D016686:Monocrotaline; D009929:Organ Size / Q000187:drug effects; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013928:Thromboxane A2 / Q000096:biosynthesis; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D002723:Chlorobenzoates; D011763:Pyrrolizidine Alkaloids; C053557:lodelaben; D013928:Thromboxane A2; D016686:Monocrotaline; D011464:Epoprostenol; D007703:Peptidyl-Dipeptidase A; D010196:Pancreatic Elastase; D010959:Tissue Plasminogen Activator; D006909:Hydroxyproline