Mechanisms of xenobiotic-induced biliary inflammation and fibrosis

描述（由申请人提供）： 摘要胆汁淤积性肝病是由胆管上皮细胞损伤引起的。该提案的广泛，长期目标是阐明外源性诱导的胆汁淤积引起炎症和纤维化的机制。流行病学研究将人类暴露于环境外源性物质与胆汁淤积性肝病联系起来。外源性接触可引起胆管损伤和慢性胆汁淤积。胆汁淤积的病理后果包括肝实质细胞损伤、炎症和纤维化，所有这些都导致胆汁淤积性肝病患者的肝脏相关发病率和死亡率。确定外源性诱导的胆汁淤积、炎症和纤维化的机制可以确定限制胆汁淤积性肝病进展的新策略。我们的初步研究表明，组织因子（TF），凝血级联反应的主要激活剂，表达的胆管上皮细胞。我们发现TF依赖性凝血促进了急性外源性胆汁淤积性肝损伤的进展。为了确定TF是否有助于胆道纤维化，我们建立了慢性外源性诱导的胆道炎症和纤维化的小鼠模型。给小鼠喂食含有0.1% α-萘异硫氰酸酯的饲料，α-萘异硫氰酸酯是一种异生物质，其独特的肝脏代谢导致选择性胆管上皮细胞损伤。喂食ANIT饮食的小鼠肝脏的细胞和组织病理学变化类似于原发性胆汁性肝硬化。我们的初步研究表明，全身高凝状态的小鼠喂养的ANIT饮食是TF依赖性的。在表达正常TF水平的1%的低TF小鼠中，神经元活化、胆管损伤和胶原沉积显著减少。这些结果形成了该提议的基础，该提议将检验由胆管上皮细胞表达的TF产生凝血蛋白酶的假设，所述凝血蛋白酶通过激活蛋白酶激活受体而促进外源性诱导的胆汁淤积中的炎症和纤维化。这一假设将利用各种遗传策略、骨髓移植以及体内和体外方法的组合进行测试。胆汁淤积性肝病患者明显的高凝状态与TF由胆管上皮细胞表达的观察结果一致。为此，更好地了解TF依赖性凝血在外源性胆汁淤积中导致炎症和纤维化的机制，可能会导致治疗胆汁淤积性肝病患者的新策略。 公共卫生相关性： 某些肝脏疾病与凝血因子的过度活动有关。肝病的进展与环境化学品暴露有关。该项目的目的是确定凝血系统在化学品暴露引起的肝病进展中的作用。

DESCRIPTION (provided by applicant): Abstract Damage to bile duct epithelial cells causes cholestatic liver disease. The broad, long term goal of this proposal is to elucidate the mechanism whereby xenobiotic-induced cholestasis causes inflammation and fibrosis. Epidemiological studies link human exposure to environmental xenobiotics and cholestatic liver disease. Xenobiotic exposure can cause bile duct injury and chronic cholestasis. The pathologic consequences of cholestasis include liver parenchymal cell injury, inflammation and fibrosis, all of which contribute to liver- related morbidity and mortality in patients with cholestatic liver disease. Determining mechanisms of xenobiotic-induced cholestasis, inflammation and fibrosis could identify novel strategies to limit the progression of cholestatic liver disease. Our preliminary studies indicate that tissue factor (TF), the primary activator of the coagulation cascade, is expressed by bile duct epithelial cells. We found that TF-dependent coagulation contributed to the progression of acute, xenobiotic-induced cholestatic liver injury. To determine whether TF contributes to biliary fibrosis, we established a mouse model of chronic xenobiotic-induced biliary inflammation and fibrosis. Mice were fed a diet containing 0.1% alpha-naphthylisothiocyanate, a xenobiotic for which unique hepatic metabolism causes selective bile duct epithelial cell injury. Cellular and histopathological changes in livers of mice fed the ANIT diet resembled primary biliary cirrhosis. Our preliminary studies indicate that systemic hypercoagulability in mice fed the ANIT diet is TF-dependent. Neutrophil activation, bile duct injury and collagen deposition were significantly reduced in low TF mice, which express 1% of normal TF levels. These results form the basis of this proposal, which will test the hypothesis that TF expressed by bile duct epithelial cells generates coagulation proteases that promote inflammation and fibrosis in xenobiotic-induced cholestasis by activating protease activated receptors. This hypothesis will be tested utilizing various genetic strategies, bone marrow transplantation, and a combination of in vivo and in vitro approaches. The apparent hypercoagulability of patients with cholestatic liver disease is consistent with the observation that TF is expressed by the bile duct epithelial cells. To this end, a greater understanding of the mechanisms whereby TF-dependent coagulation contributes to inflammation and fibrosis in xenobiotic-induced cholestasis could lead to novel strategies to treat patients with cholestatic liver disease. PUBLIC HEALTH RELEVANCE: Certain liver diseases are associated with excessive activity of blood clotting factors. The progression of liver disease is linked to environmental chemical exposure. The purpose of this project is to determine the role of the blood clotting system in the progression of liver disease caused by chemical exposure.