Monocrotaline pneumotoxicity in mice.
Lung injury induced in rats by the pyrrolizidine alkaloid monocrotaline is a well-documented model of pulmonary hypertension. To our knowledge, however, monocrotaline-induced cardiopulmonary injury has rarely been described and has never been quantitated in mice. In the present study, adult male mice received 2.4, 4.8, or 24.0 mg monocrotaline/kg body weight/day in the drinking water continuously for 6 weeks. These doses represent 1, 2, and 10 times the severely pneumotoxic regimen in rats. Pulmonary endothelial function was monitored by right lung angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Light and electron microscopy were performed on the left lungs. Cardiac right ventricular hypertrophy was evaluated by the right ventricle to left ventricle plus septum weight ratio (RV/LV + S). Monocrotaline-treated mice exhibited a dose-dependent decrease in lung ACE and PLA activities and an increase in PGI2 and TXA2 production, indicative of endothelial dysfunction. However, these responses were significant only after the highest monocrotaline dose. Light and electron microscopy revealed dose-dependent pulmonary inflammatory and exudative reactions. Unlike previous studies in rats, however, monocrotaline-treated mice developed relatively little lung fibrosis, cardiomegaly, or right ventricular hypertrophy, and no occlusive medial thickening of the pulmonary arteries, even at the highest dose level. These and previous data indicate that there are quantitative biochemical and qualitative morphological differences between mice and rats with respect to monocrotaline pneumotoxicity. Furthermore, in monocrotaline-treated mice (but not in rats) there appears to be a dissociation between lung endothelial dysfunction and inflammation on the one hand, and pulmonary hypertension and fibrosis on the other.
Molteni
A
A
Department of Pathology, Northwestern University School of Medicine, Chicago, IL 60611.
Ward
W F
WF
Ts'ao
C H
CH
Solliday
N H
NH
D000818:Animals; D011464:Epoprostenol / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008854:Microscopy, Electron; D016686:Monocrotaline; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D010947:Plants, Toxic; D010960:Plasminogen Activators / Q000378:metabolism; D011763:Pyrrolizidine Alkaloids / Q000633:toxicity*; D012674:Senecio; D013928:Thromboxane A2 / Q000096:biosynthesis
D011763:Pyrrolizidine Alkaloids; D013928:Thromboxane A2; D016686:Monocrotaline; D011464:Epoprostenol; D007703:Peptidyl-Dipeptidase A; D010960:Plasminogen Activators