Mechanisms of xenobiotic-induced biliary inflammation and fibrosis

异生素诱导胆道炎症和纤维化的机制

• 批准号: 7728072
• 负责人: James P Luyendyk
• 金额: $ 50.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728072
• 关键词: Acute; Bile Acids; Bile Duct Epithelium; Bile fluid; Biliary; Blood; Blood Clot; Blood Coagulation Factor; Blood coagulation; Bone Marrow Transplantation; Cells; Chemical Exposure; Cholestasis; Chronic; Coagulation Process; Collagen; Data; Deposition; Development; Diet; Disease; Epidemiologic Studies; Epithelial Cells; Exposure to; Factor Xa; Fibrin; Fibroblasts; Fibrosis; Generations; Genetic; Goals; Growth Factor; Hepatic; Hepatitis; Hepatocyte; In Vitro; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Integral Membrane Protein; Intrahepatic bile duct; Lead; Ligation; Link; Liver; Liver Fibrosis; Liver diseases; Liver parenchyma; Mediator of activation protein; Metabolism; Modeling; Morbidity - disease rate; Mus; Myofibroblast; Necrosis; Neutrophil Activation; Normal tissue morphology; PAR-1 Receptor; PAR-2 Receptor; Pathogenesis; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Primary biliary cirrhosis; Proliferating; Proteinase-Activated Receptors; Regulation; Relative (related person); Role; Rupture; Sclerosing Cholangitis; Signal Transduction; Source; Staging; System; Technology; Testing; Thrombin; Thrombophilia; Thromboplastin; Transforming Growth Factors; Xenobiotics; abstracting; base; bile duct; cell injury; cell type; chemokine; cytokine; environmental chemical exposure; exposed human population; feeding; in vivo; injured; intrahepatic; macrophage; mortality; mouse model; neutrophil; novel; novel strategies; protein expression; public health relevance; receptor

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.

描述（由申请人提供）： 对胆管上皮细胞的抽象损害会导致胆汁淤积性肝病。该提案的广泛，长期的目标是阐明异种生物诱导的胆汁淤积的机制，引起炎症和纤维化。流行病学研究将人类暴露于环境异种生物和胆汁淤积性肝病。异生物暴露会导致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，所有这些都导致胆固醇肝病患者的肝脏相关发病率和死亡率。确定异种生物诱导的胆汁淤积，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型策略。我们的初步研究表明，组织因子（TF）是凝血级联反应的主要激活因子，由胆管上皮细胞表达。我们发现，TF依赖性凝血有助于急性，异种生物诱导的胆汁淤积性肝损伤。为了确定TF是否有助于胆汁纤维化，我们建立了一种慢性异种生物诱导的胆汁炎症和纤维化的小鼠模型。给小鼠喂食含有0.1％α-萘甲硫氰酸盐的饮食，这是一种异源生物，独特的肝代谢会导致选择性胆管上皮细胞损伤。小鼠肝脏的细胞和组织病理学变化类似于原发性胆汁肝硬化。我们的初步研究表明，喂养ANIT饮食的小鼠全身性高凝性是TF依赖性的。在低TF小鼠中，中性粒细胞活化，胆管损伤和胶原蛋白沉积显着降低，该小鼠表达正常TF水平的1％。这些结果构成了该提案的基础，该基础将检验以下假设：胆管上皮细胞表达的TF产生凝血蛋白酶，可通过激活蛋白酶激活的受体来促进异生物生物诱导的胆汁淤积的炎症和纤维化。通过各种遗传策略，骨髓移植以及体内和体外方法的组合，将对这一假设进行检验。胆固性肝病患者的明显高凝性与观察到TF由胆管上皮细胞表达的观察结果一致。为此，对TF依赖性凝血的机制有更多的理解有助于异生物生物诱导的胆汁淤积的炎症和纤维化，这可能会导致治疗胆固性肝病患者的新型策略。 公共卫生相关性： 某些肝脏疾病与血液凝血因子的过度活性有关。肝病的进展与环境化学暴露有关。该项目的目的是确定血液凝结系统在化学暴露引起的肝病进展中的作用。