Platelets and the puzzles of pulmonary pyrrolizidine poisoning.

Pyrrolizidine alkaloids such as monocrotaline (MCT) are toxic plant constituents which poison livestock and humans. Low doses of MCT given to rats result in cardiopulmonary pathophysiologic sequelae similar to forms of chronic pulmonary hypertension in man. This provides a useful model of human disease. The toxicology of MCT is complex, and the mechanisms by which it causes lung injury, pulmonary hypertension, and right heart enlargement have remained elusive despite intensive study by numerous investigators. MCT is bioactivated by the liver to a reactive, electrophilic pyrrole (MCTP) that travels via the circulation to the lung, where injury results. When low, intravenous doses of MCTP are given to rats, a delay of several days occurs before lung injury and pulmonary hypertension become apparent. Moderate depletion of blood platelets around the time of the onset of lung injury lessens the subsequent development of right ventricular enlargement, suggesting a reduction in the pulmonary hypertensive response to MCTP. This observation prompted a study of the role of platelet-derived mediators in the cardiopulmonary response to MCTP. A stable analog of thromboxane A2(TxA2) caused a greater increase in right ventricular pressure in MCTP-treated rats compared to controls, and lungs isolated from MCTP-treated rats produced more TxB2 than those of controls. However, administration of drugs that either inhibited thromboxane synthesis or antagonized the effects of thromboxane did not afford protection from MCTP in vivo. Serotonin (5HT), another vasoactive mediator released by platelets, caused an exaggerated vasoconstrictor response in isolated lungs from rats treated with MCTP. Moreover, removal and inactivation of circulating 5HT by the pulmonary vasculature was impaired by treatment of rats with MCTP. However, administration of 5HT receptor antagonists did not attenuate the cardiopulmonary effects of MCTP in vivo. These results suggest that neither TxA2 nor 5HT is the sole mediator of the pneumotoxicity due to MCTP. Thus, the mechanism by which platelets are involved in the pathogenesis of the pneumotoxic response to MCTP remains an unsolved puzzle.