Role of leukotriene B4 in monocrotaline-induced pulmonary hypertension

Abstract

Monocrotaline (MCT) causes lung inflammation and chronic pulmonary hypertension associated with lung vascular thickening in rats. We hypothesized that leukotriene B4 (LTB4) and LTB4-induced accumulation of leukocytes in the lung play a role in MCT-induced lung disease, and therefore measured LTB4 and myeloperoxidase (MPO) levels in lung tissue of MCT-treated rats. Next, we examined the effect of an orally active LTB4 receptor antagonist (ONO4057) on MPO levels in lung tissue, on pulmonary hypertension, and on pulmonary vascular remodeling induced by MCT. Lung LTB4 and MPO levels had increased by 3 days after MCT injection. In the ONO4057-treated MCT rats, lung MPO levels were significantly lower than in the rats given MCT but not ONO4057. By the third week after injection. MCT had caused increases in mean pulmonary arterial pressure, in the ratio of right ventricular weight to left ventricle+septum weight (RV/[VS + S]), and in media wall thickness of the muscular arteries of the lung. Treatment with ONO4057, either for 3 weeks or during the first week after MCT injection, significantly reduced pulmonary hypertension, right ventricular hypertrophy, and lung vascular thickening induced by MCT. These results indicate that ONO4057 reduces both the accumulation of leukocytes in lung tissue and the chronic pulmonary hypertension induced by MCT, and they suggest a role for LTB4 in the inflammatory process that contributes to pulmonary hypertension and lung vascular remodeling induced by MCT in rats.