Mechanisms and Pathology of Monocrotaline Pulmonary Toxicity

Abstract

Monocrotaline (MCT) is an 11-membered macrocyclic pyrrolizidine alkaloid (PA) that causes a pulmonary vascular syndrome in rats characterized by proliferative pulmonary vasculitis, pulmonary hypertension, and cor pulmonale. Current hypotheses of the pathogenesis of MCT-induced pneumotoxicity suggest that MCT is activated to a reactive metabolite(s) in the liver and is then transported by red blood cells (RBCs) to the lung, where it initiates endothelial injury. While several lines of evidence support the requirement of hepatic metabolism for pneumotoxicity, the mechanism and relative importance of RBC transport remain undetermined. The endothelial injury does not appear to be acute cell death but rather a delayed functional alteration that leads to disease of the pulmonary arterial walls by unknown mechanisms. The selectivity of MCT for the lung, as opposed to that of other primarily hepatotoxic PAs, appears likely to be a consequence of the differences in hepatic metabolism and blood kinetics of MCT. A likely candidate for a reactive metabolite of MCT is the dehydrogenation product monocrotaline pyrrole (MCTP). Secondary or phase II metabolism of MCT through glutathione (GSH) conjugation has been characterized recently and appears to represent a detoxification pathway. The role of inflammation in the progression of MCT-induced pulmonary vascular disease is uncertain. Both perivascular inflammation and platelet activation have been proposed as processes contributing to the response of the vascular media. This review presents the experimental evidence supporting these hypotheses and outlines additional questions that arise from them.

Pulmonary hypertension

“…Monocrotaline (MCT) 2 is an 11-membered macrocyclic diester member of the pyrrolizidine alkaloid family of plant toxins that produces a delayed onset yet progressive pulmonary vascular disease resulting in pulmonary hypertension (PH) in Sprague-Dawley rats [1][2][3]. Therefore, MCT-induced PH has been used as a model for the study of chronic pulmonary vascular diseases in humans since 1961 [4].…”

“…Therefore, MCT-induced PH has been used as a model for the study of chronic pulmonary vascular diseases in humans since 1961 [4]. Nevertheless, the exact mechanism by which MCT causes pulmonary toxicity is still not completely understood [3]. Considerable efforts have been made by many research groups to elucidate the mechanism [5][6][7][8].…”

“…However, they can be accurately classified and properly assigned by the PCA/PLS method. The fact that different tissue types can be accurately divided into their corresponding groups by the NIR and PCA/PLS methods suggests that chemical alterations and mechanisms of pulmonary vascular remodeling and PH induced by MCT are different from those induced by CH.Ó 2009 Elsevier Inc. All rights reserved.Monocrotaline (MCT) 2 is an 11-membered macrocyclic diester member of the pyrrolizidine alkaloid family of plant toxins that produces a delayed onset yet progressive pulmonary vascular disease resulting in pulmonary hypertension (PH) in Sprague-Dawley rats [1][2][3]. Therefore, MCT-induced PH has been used as a model for the study of chronic pulmonary vascular diseases in humans since 1961 [4].…”

Support of sinusoidal endothelial cell glutathione prevents hepatic veno-occlusive disease in the rat

“…[2][3][4] Monocrotaline, which is used in the model in this article, is one of the best-characterized toxins that cause HVOD. It is a pyrrolizidine alkaloid that is metabolically activated by hepatic P-450s to the toxic, alkylating pyrrole, dehydromonocrotaline (see review 5 ). This reactive metabolite is detoxified by glutathione conjugation 3,6,7 The current study examines whether intraportal infusion of GSH can prevent HVOD in vivo and addresses the mechanism of protection.…”

Monocrotaline-induced pulmonary hypertension correlates with upregulation of connective tissue growth factor expression in the lung

“…Monocrotaline (MCT), a pyrrolizidine alkaloid from Crotalaria spectabilis, is activated metabolically in the liver to monocrotaline pyrrole which is then transported to the lungs and becomes pneumotoxic (Wilson et al, 1992). It is thought to induce lung reactions such as interstitial edema, inflammation, hemorrhage and fibrosis (Kay and Heath, 1969).…”