Monocrotaline pneumotoxicity in mice |
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Authors: | Agostino Molteni William F Ward Chung-hsin Ts’ao Norman H Solliday |
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Institution: | 1. Department of Pathology, Northwestern University of Medical School, 303 East Chicago Avenue, I 60611, Chicago, USA 2. Department of Radiology, Northwestern University School of Medicine, 60611, Chicago, IL 3. Christ Hospital, 60453, Oak Lawn, IL, USA
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Abstract: | 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). Monocrotalinetreated 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 dosedependent 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. |
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Keywords: | Monocrotaline Angiotensin converting enzyme Plasminogen activator Prostacyclin Thromboxane |
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