The objective of this proposal is the study of the pharmacology and toxicology of the pulmonary endothelium. The understanding of what toxic events occur at the endothelium, and how do these events affect the functioning of the rest of the lungs and the right heart are twin aspects of this objective. The endothelial toxin to be studied is monocrotaline, a pyrrolizidine alkaloid. Pyrrolizidine alkaloids are major and ubiquitous public health problems. Monocrotaline produces hepatomegaly and veno-occlusive disease of the liver. Hepatic metabolites of it affect the lung, producing pulmonary arterial hypertension and right ventricular hypertrophy. These conditions are preceded by changes in the pulmonary endothelium. What are the pneumotoxic metabolites of monocrotaline? What endothelial functions do they affect? How do disturbances of these functions affect the cardiopulmonary system? Obtaining answers to these three questions comprise the specific aims of the proposal. A theory to be tested is that the pneumotoxic metabolites are acyclic monoesters of dehydroretronecine and that these metabolites irreversibly inhibit serotonin removal by the pulmonary endothelium, without affecting the serotonin S2 receptors located on the vascular smooth muscle that mediate vasoconstriction. Studies will be carried out on: isolated lungs of rats exposed in vivo to monocrotaline or the synthesized putative metabolites of monocrotaline; isolated perfused lungs of rats untreated in vivo; and isolated pulmonary arterial and pulmonary venous segments. At the conclusion of the work, we should have a better understanding of the mechanisms of pneumotoxicity of monocrotaline, and a better understanding of how the pulmonary vascular and right heart changes produced by pyrrolizidines may be attenuated.
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