Pyrrolizidine alkaloids (PAs) are plant derived toxins that have been shown to contaminate human and animal food sources. This contamination is responsible for numerous toxic syndromes and PAs are known mutagens and carcinogens. The PA monocrotaline (MCT) is of particular interest because of its toxic effects on the lungs and heart. Rats administered MCT or its metabolite monocrotaline pyrrole (MCTP), a known alkylating agent, develop a pulmonary vascular syndrome that is widely used as a model to study the pathogenesis of human pulmonary hypertension. Pulmonary hypertension is a common pathologic sequelae of a variety of chronic pulmonary diseases, several of which are associated with environmental or occupational exposure to pneumotoxic chemicals. While much is known regarding the progression of pulmonary vascular lesions leading to hypertension and cor pulmonale, the initiating mechanisms in pulmonary hypertension caused by MCT and other pathologic processes are poorly characterized. current research suggests the following hypothesis of MCT's action: Monocrotaline is activated in the liver to a metabolite, that is sequestered in red blood cells (RBC')s where it is stabilized during transport to the lung and causes non-cytotoxic but irreversible endothelial injury. this injury results in deficiency in the endothelial fluid barrier and the resultant increased fluid transudation stimulates the arteriolar response that leads to hypertension. We plan to characterize MCT metabolites, the nature and mechanism of RBC sequestration of MCT metabolites, determining whether the RBC plays an active or passive role in the transport process, documenting the nature, progression and location of permeability changes induced in the lung by MCT treatment and characterizing the potential pathogenetic and toxicologic mechanisms of endothelial cell injury. We will use an integrative approach to these questions using biosynthesized, radiolabeled MCT and its metabolites for experiments in vivo and in isolated organ systems, and cell culture, as well as molecular biological techniques to determine the mechanisms of MCT metabolism, transport, and target cell toxicity in the lung.
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