Abstract：
Cholestasis is a hepatobiliary disorder characterized by the excessive accumulation of toxic bile acids in hepatocytes, leading to cholestatic liver injury (CLI) through multiple pathogenic inflammatory pathways. Currently, there are limited therapeutic options for the management of cholestasis and associated CLI; therefore, new options are urgently needed. Pirfenidone (PF), an oral bioavailable pyridone analog, is used for the treatment of idiopathic pulmonary fibrosis. PF has recently demonstrated diverse potential therapeutic activities against different pathologies. Accordingly, the present study adopted the α-naphthyl isothiocyanate (ANIT)-induced CLI model in mice to explore the potential protective impact of PF and investigate the underlying mechanisms of action. PF intervention markedly reduced the serum levels of ALT, AST, LDH, total bilirubin, and total bile acids, which was accompanied by a remarkable amelioration of histopathological lesions induced by ANIT. PF also protected the mice against ANIT-induced redox imbalance in the liver, represented by reduced MDA levels and elevated GSH and SOD activities. Mechanistically, PF inhibited ANIT-induced downregulated expressions of the farnesoid X receptor (FXR), as well as the bile salt export pump (BSEP) and the multidrug resistance-associated protein 2 (MRP2) bile acid efflux channels. PF further repressed ANIT-induced NF-κB activation and TNF-α and IL-6 production. These beneficial effects were associated with its ability to dose-dependently inhibit Wnt/GSK-3β/β-catenin/cyclin D1 signaling. Collectively, PF protects against ANIT-induced CLI in mice, demonstrating powerful antioxidant and anti-inflammatory activities as well as an ability to oppose BA homeostasis disorder. These protective effects are primarily mediated by modulating the interplay between FXR, NF-κB/TNF-α/IL-6, and Wnt/β-catenin signaling pathways.
摘要：
胆汁淤积是一种肝胆疾病，其特征是肝细胞中毒性胆汁酸的过度积累，通过多种致病炎症途径导致胆汁淤积性肝损伤（CLI）。目前,胆汁淤积和相关CLI的治疗选择有限；因此，迫切需要新的选择。吡非尼酮(PF),口服生物可利用吡啶酮类似物，用于治疗特发性肺纤维化。PF最近针对不同病理表现出多种潜在的治疗活性。因此，本研究采用异硫氰酸萘酯（ANIT）诱导的小鼠CLI模型，以探讨PF的潜在保护作用并探讨其潜在的作用机制。PF干预明显降低血清ALT水平，AST,LDH,总胆红素,和总胆汁酸，伴随着由ANIT引起的组织病理学病变的显着改善。PF还保护小鼠免受ANIT诱导的肝脏氧化还原失衡，以MDA水平降低和GSH和SOD活性升高为代表。机械上,PF抑制ANIT诱导的法尼醇X受体（FXR）的表达下调，以及胆盐出口泵（BSEP）和多药耐药相关蛋白2（MRP2）胆汁酸流出通道。PF进一步抑制ANIT诱导的NF-κB激活以及TNF-α和IL-6的产生。这些有益作用与其剂量依赖性地抑制Wnt/GSK-3β/β-连环蛋白/细胞周期蛋白D1信号传导的能力有关。总的来说，PF保护小鼠免受ANIT诱导的CLI，表现出强大的抗氧化和抗炎活性以及对抗BA稳态障碍的能力。这些保护作用主要通过调节FXR之间的相互作用来介导，NF-κB/TNF-α/IL-6和Wnt/β-catenin信号通路。
