Improvement of hepatic fibrosis by leukotriene inhibition in cholestatic rats

Abstract

Chronic liver disease is characterized by inflammation and fibrosis. Angiogenesis which leading to new vasculature may have prognostic value in disease progression. This study examined the implication of 5-lipoxygenase pathway and angiogenic factors in hepatic fibrosis progression and whether, the inhibition of arachidonic acid cascade product (cysteinyl leukotrienes) can represent a potential target for therapy. Cholestasis and subsequent fibrosis was induced by common bile duct ligation and resection (BDL) for 5 weeks in rats. After surgery, Cysteinyl leukotrienes antagonist (montelukast) was orally and daily administrated (10 mg/kg) for 34 days. Sham operated and drug control groups received either saline or montelukast immediately after operation. BDL significantly increased liver hydroxyproline (Hp), nuclear factor kappa B (NF-(k )ss), transforming growth factor beta (TGF-ss), tissue inhibitor metalloproteinase (TIMP-1), vascular endothelial growth factor (VEGF), and reduced the level of matrix metalloproteinase 9 (MMP-9). On the other hand, montelukast treatment reversed all these biochemical parameters and ameliorated histopathological changes which previously induced by BDL. Findings of the present study suggest that montelukast treatment may favor collagenolytic activity through modulating hepatic expression of TGFss-, NF-(k)ss, and MMP-9/TIMP-1 ratio. Amelioration of necroinflammatory liver injury and fibrogenesis may support such assumption.