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Pulmonary endothelial and bronchiolar epithelial lesions induced by 4-ipomeanol in mice
Abstract:
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.
Insights
Toxic furan 4-ipomeanol causes pulmonary edema and lung injury in mice. Endothelial cells and bronchiolar cells are early targets, with endothelial damage driving edema.
Area of Science:
- Toxicology
- Pulmonary Pathology
- Cell Biology
Background:
- 4-ipomeanol is a toxic furan compound.
- Pulmonary edema and bronchiolar injury are potential health concerns.
Purpose of the Study:
- To investigate the morphogenesis of pulmonary edema and bronchiolar injury induced by 4-ipomeanol.
- To identify the cellular targets and mechanisms of 4-ipomeanol toxicity in the mouse lung.
Main Methods:
- Combined light and transmission electron microscopy were used.
- Weanling male CD-1 mice were administered 4-ipomeanol via intraperitoneal injection.
- Tissues were examined at various time points from 2 to 360 hours post-treatment.
Main Results:
- Interstitial edema and endothelial cell damage were observed as early as 2 hours post-treatment.
- Severe endothelial damage, characterized by endoplasmic reticulum dilation and mitochondrial swelling, peaked between 12-24 hours, coinciding with alveolar edema.
- Nonciliated bronchiolar epithelial cell damage, including necrosis and sloughing, occurred from 36-48 hours.
- Repair processes were complete by 240 hours.
Conclusions:
- The endothelium of capillaries and small veins, and nonciliated bronchiolar epithelial cells, are primary targets of 4-ipomeanol toxicity.
- Endothelial cell injury is a key factor in the development of 4-ipomeanol-induced pulmonary edema.
- Pulmonary endothelial cells may metabolize 4-ipomeanol into toxic compounds.