Monocrotaline-induced pulmonary endothelial dysfunction in rats.
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 (PGI2) 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, PGI2 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 99mTc 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.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004727:Endothelium / Q000187:drug effects; D011464:Epoprostenol / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000648:ultrastructure; D055370:Lung Injury; D008297:Male; D008854:Microscopy, Electron; D016686:Monocrotaline; D009929:Organ Size / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010960:Plasminogen Activators / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D011763:Pyrrolizidine Alkaloids; D016686:Monocrotaline; D011464:Epoprostenol; D007703:Peptidyl-Dipeptidase A; D010960:Plasminogen Activators