Chronic pulmonary hypertension--the monocrotaline model and involvement of the hemostatic system.
Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right heart hypertrophy. The lesions induced by MCT(P) administration in rats are similar to those observed in certain chronic pulmonary vascular diseases of people. This review begins with a synopsis of the hemostatic system, emphasizing the role of endothelium since endothelial cell dysfunction likely underlies the pathogenesis of MCT(P)-induced pneumotoxicity. MCT toxicology is discussed, focusing on morphologic, pulmonary mechanical, hemodynamic, and biochemical and molecular alterations that occur after toxicant exposure. Fibrin and platelet thrombosis of the pulmonary microvasculature occurs after administration of MCT(P) to rats, and several investigators have hypothesized that thrombi contribute to the lung injury and pulmonary hypertension. The evidence for involvement of the various components of the hemostatic system in MCT(P)-induced vascular injury and remodeling is reviewed. Current evidence is consistent with involvement of platelets and an altered fibrinolytic system, yet much remains to be learned about specific events and signals in the vascular pathogenesis.
Schultze
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AE
Department of Pathology, College of Veterinary Medicine, University of Tennessee, Knoxville, USA.
Roth
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RA
D000818:Animals; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced* / Q000209:etiology; D017380:Hypertrophy, Right Ventricular / Q000097:blood / Q000139:chemically induced* / Q000209:etiology; D016686:Monocrotaline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000633:toxicity*; D010946:Plants, Medicinal / Q000009:adverse effects; D010947:Plants, Toxic / Q000009:adverse effects; D051381:Rats
C014114:monocrotaline pyrrole; D016686:Monocrotaline