Mechanisms of xenobiotic-induced biliary inflammation and fibrosis

描述(由申请人提供)： 摘要胆管上皮细胞损伤可导致胆汁淤积性肝病。这项建议的广泛和长期目标是阐明异物诱导的胆汁淤积导致炎症和纤维化的机制。流行病学研究将人类接触环境中的外来物质与胆汁淤积性肝病联系起来。异种生物暴露可导致胆管损伤和慢性胆汁淤积。胆汁淤积症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与肝脏相关的发病率和死亡率。确定异物诱导的胆汁淤积、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，凝血级联的主要激活物组织因子(TF)是由胆管上皮细胞表达的。我们发现，依赖于转铁蛋白的凝血在异物诱导的急性淤胆性肝损伤的进展中起作用。为了确定转铁蛋白是否参与了胆道纤维化，我们建立了一种慢性异种生物诱导的胆道炎症和纤维化的小鼠模型。小鼠的饲料中含有0.1%的α-萘基异硫氰酸酯，这是一种异物，其独特的肝脏代谢会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变。我们的初步研究表明，喂食ANIT饮食的小鼠的全身高凝状态是Tf依赖的。中性粒细胞活化、胆管损伤和胶原沉积在低转铁组显著减少，低转铁组仅为正常转铁组的1%。这些结果构成了这一提议的基础，它将检验这样一种假设，即胆管上皮细胞表达的转铁蛋白通过激活蛋白酶激活的受体而产生凝血酶，从而促进异物诱导的胆汁淤积的炎症和纤维化。这一假说将利用各种遗传策略、骨髓移植以及体内和体外相结合的方法进行验证。胆汁淤积性肝病患者的明显高凝状态与胆管上皮细胞表达转铁蛋白的观察结果一致。为此，更好地了解异物诱导的胆汁淤积症中TF依赖的凝血促进炎症和纤维化的机制可能会导致治疗胆汁淤积性肝病的新策略。 公共卫生相关性： 某些肝病与凝血因子的过度活跃有关。肝病的发展与环境中的化学物质接触有关。该项目的目的是确定血液凝结系统在化学物质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.