Monocrotaline (MCT) is a pyrrolizidne alkaloid that causes injury accompanied by pulmonary hyepertension and right ventricular hypertrophy in experimental animals. Its pathophysiology shares much in common with primary pulmonary hypertension (PPH) in humans, and thus the MCT-treated rat is a good animal model to study PPH. A reactive pyrrole metabolite (MCTP) is thought to be the proximate toxicant, but its mechanism of action is unknown. The onset of injury after a single dose of MCT or chemically synthesized MCTP is delayed 4-7 days. The changes in pulmonary morphology after MCT or MCTP include vasculitis and fibrinoid necrosis, nuetrophil (PMN) infiltration, accumulation of platelets and fibrin in the vessels, and mononuclear cell infiltration. Also, immunoglobulin deposits are found in the pulmonary tissues 7 and 14 days after MCTP but not at 3 days. These lesions are considerable hallmarks of injury mediated by the immune system. The immunosuppressants cyclosporin A and dexamethasone protect against the cardiopulmonary effects of MCTP. These results suggest that MCTP acts indirectly to produce pulmonary injury, perhaps through immune-mediated mechanisms. Accordingly, the goal of the p roposed experiments is to evaluate the role of the immune system in the cardiopulmonary effects of MCTP. Experiments will be performed to test whether passively transferred serum or adoptively transferred lymphocytes from MCTP-treated donors into recipient rats produces injury or alters the onset of lung injury in the recipients. Lymphocytes from MCTP-treated rats will be assessed for their ability to respond to pulmonary antigens in the macrophage migration inhibition test and in the lymphocyte transformation assay. The ability of anti-lymphocyte serum to alter MCTP cardiopulmonary effects will also be evaluated. In addition, expeeriments will be performed to evaluate the role of the complement system and the PMN in causing the injury. The importance of toxic metabolites generated in the lung by phagocytes after MCTP treatment will also be assessed. These studies are unique since they will examine the role of immune effector systems that mediate pulmonary damage in a model of progressive and relatively long-term cardiopulmonary injury. The results will further our understanding of plulmonary vascular disease and chronic pulmonary hypertension. Such knowledge may lead to new measures to prevent or to treat humans suffering from these diseases.
