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Am J Pathol. 1985 Jan;118(1):66-75.

Pulmonary endothelial and bronchiolar epithelial lesions induced by 4-ipomeanol in mice.


The morphogenesis of pulmonary edema and bronchiolar injury induced by the toxic furan, 4-ipomeanol, was studied by combined light and transmission electron microscopy. Weanling male CD-1 mice received 47 mg 4-ipomeanol/kg body weight by intraperitoneal injection and were studied at intervals from 2 to 360 hours after treatment. Interstitial edema associated with damaged endothelial cells was observed as early as 2 hours after treatment. The most severe endothelial damage was observed from 12 to 24 hours after treatment and occurred in association with alveolar edema. Capillary endothelial cell damage was characterized by marked dilation of endoplasmic reticulum and perinuclear envelopes, marked swelling of mitochondria, separation of cytoplasmic processes from other endothelial cells and their basal laminae, and occasional disruptions in the plasmalemma. Endothelial cell lesions in small caliber veins were similar but less pronounced as compared with the alterations observed in capillary endothelium. Minimal changes were present in alveolar epithelial cells. Damage to nonciliated bronchiolar epithelial cells was first observed at 4 hours after injection. The most severe changes in nonciliated cells occurred from 36 to 48 hours after treatment and included swelling of endoplasmic reticulum, necrosis, and sloughing. There was also necrosis and sloughing of ciliated bronchiolar epithelial cells. Endothelial and bronchiolar epithelial repair and resolution of the alveolar edema were complete by 240 hours after treatment. It is concluded that the endothelium lining capillaries and small veins, in addition to the nonciliated bronchiolar epithelial cell, are early targets in the development of 4-ipomeanol toxicity in the mouse and that the endothelial cell injury plays a major role in the development of pulmonary edema in this species. The results further suggest the possibility that pulmonary endothelial cells have the capability of metabolizing xenobiotic compounds such as 4-ipomeanol to form ultimate toxins.

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