Chronic pulmonary hypertension‐the monocrotaline model and involvement of the hemostatic system

Abstract

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.

Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavailability

“…Closed-chest right-and left-heart microcardiac catheterization in live animals detected pulmonary hypertension in all sickle mice studied but not in hemizygous colony controls or wild-type controls. The pulmonary hypertension occurred spontaneously, unlike the need for experimental triggers in other animal models, [33][34][35][36] and without evidence of thrombosis or major vascular remodeling. The pulmonary hypertension was mediated by a functional impairment in endothelial-dependent vasodilation, NO resistance, and increased vasoconstrictor tone.…”

Possible Involvement of Mitochondrial Energy-Producing Ability in the Development of Right Ventricular Failure in Monocrotaline-Induced Pulmonary Hypertensive Rats

“…A rise in pulmonary artery hypertension induces right ventricular hypertrophy and right ventricular failure and eventually leads to premature death. It is well known that a single subcutaneous administration of the pyrrolizidine alkaloid monocrotaline to rats causes cardiovascular and pulmonary disorders similar to those seen in patients with pulmonary artery hypertension (1,2), including severe right ventricular hypertrophy (3,4) and right ventricular failure (5 -8). Despite extensive studies, the fundamental mechanisms responsible for the development and progression of right ventricular failure have not been fully elucidated.…”

International Hypoxia Symposium (13th) for the Publishing of the Conference Proceedings for 2003 Conference

“…This is of importance because different levels of growlh factors and their receptors can modulate/activate the HIF pathway through stimulation of phosphorylation cascades. The three broad subfamilies of the mitogen-activated protein kinase (MAPK) cascades, namely the c-Jun NHj-terminal kinases (JNKs), p38 MAPKs and the extracellular signal-regulated kinases (Erks) have been shown to be involved in the regulation of the HIF-pathway (2,41,109,118,135). Interestingly, although HIF-la is a highly phosphorylated protein and two Erkl/Erk2 MAPK consensus sites (PXSP) ex-ist on the human HIF-1 a (positions 515 and 687), point mutations did not reveal the exact phosphorylation sites (118).…”