Mechanisms of fibrosis exacerbation by trichloroethylene in hepatic autoimmunity

描述(由申请人提供)：在美国和国外，人类接触三氯乙烯(TCE)仍然是一个紧迫的问题。近年来，三氯乙烯被归类为人类致癌物，这进一步强调了有必要完全确定三氯乙烯对人类疾病造成和加剧的潜在危害。来自啮齿动物研究的强有力的实验证据将三氯乙烯暴露与自身免疫性肝病的发展联系起来。流行病学研究证实了这种联系，研究表明，在被三氯乙烯污染的危险废物场地附近，原发性胆汁性肝硬变的患病率增加，这是一种自身免疫性肝病。然而，对并发肝脏自身免疫的患者暴露于TCE的风险了解不足，也没有现有的关于TCE影响自身免疫性肝病进展的机制的描述。长期目标是确定三氯乙烯加重持续性自身免疫介导的肝损伤导致的肝纤维化的机制。研究人员发现，在存在肝脏自身免疫的小鼠中，暴露于与职业相关的TCE暴露水平的小鼠显著增加了肝纤维化。这些研究的总体目标是确定TCE暴露对自身免疫性胆管炎小鼠模型非肥胖糖尿病(NOD).c3c4小鼠肝纤维化进展的影响，同时确定NOD.c3c4小鼠的自身免疫对TCE代谢的影响。他们的中心假设是，TCE暴露通过促进肝脏RANTES的合成而加剧了肝脏自身免疫中的肝纤维化，而自身免疫性肝病中TCE代谢的改变进一步加剧了TCE的毒性。研究人员的拨款申请包括一项关于TCE暴露对NOD.c3c4小鼠自身免疫性肝病发病机制的剂量和时间依赖影响的综合分析。反过来，这些研究利用研究小组的专业知识来确定肝脏自身免疫对TCE代谢的影响。为了能够识别TCE暴露在肝脏自身免疫中的机制生物标志物，拟议的研究利用RNA测序来识别肝脏和血白细胞中TCE暴露的差异调控基因。此外，研究人员将确定RANTES受体(CCR1/CCR5)拮抗剂Met-RANTES对TCE暴露引起的NOD.c3c4小鼠肝纤维化加剧的影响。这些研究的预期结果将是更好地了解和检测个体对三氯乙烯有害影响的易感性。此外，这些研究将提供目前尚不存在的治疗策略，以对抗自身免疫性个体中TCE加剧的纤维化反应。

DESCRIPTION (provided by applicant): Human exposure to trichloroethylene (TCE) remains a pressing concern in the United States and abroad. The categorization of TCE in recent years as a human carcinogen has further emphasized the need to completely define the potential of TCE exposure to both cause and exacerbate human disease. Strong experimental evidence from rodent studies links TCE exposure to the development of autoimmune liver disease. This connection is substantiated by epidemiological studies indicating an increased prevalence of primary biliary cirrhosis, an autoimmune liver disease, near hazardous waste sites contaminated with TCE. However, there is an insufficient understanding of the risks of TCE exposure in patients with concurrent hepatic autoimmunity, and no existing delineation of the mechanisms whereby TCE influences the progression of autoimmune liver disease. The long-term goal is to define the mechanisms whereby TCE exacerbates liver fibrosis induced by persistent autoimmune-mediated liver damage. The investigators found that exposure of mice to an occupationally-relevant TCE exposure level significantly increased liver fibrosis in mice with coexisting hepatic autoimmunity. The overall objective of these studies is to determine the effect of TCE exposure on the progression of liver fibrosis in non-obese diabetic (NOD).c3c4 mice, a mouse model of autoimmune cholangitis, and concurrently to define the impact of autoimmunity in NOD.c3c4 mice on TCE metabolism. Their central hypothesis is that TCE exposure exacerbates liver fibrosis in hepatic autoimmunity by promoting hepatic synthesis of RANTES and that TCE toxicity is further exacerbated by altered TCE metabolism in autoimmune liver disease. The investigators' grant application includes a comprehensive analysis of the dose- and time-dependent impact of TCE exposure on the pathogenesis of autoimmune liver disease in NOD.c3c4 mice. Reciprocally, these studies draw on the expertise of the investigative team to determine the effect of hepatic autoimmunity on TCE metabolism. To enable identification of mechanistic biomarkers of TCE exposure in hepatic autoimmunity, the proposed studies utilize RNA sequencing to identify genes differentially dysregulated by TCE exposure in liver and blood leukocytes. Moreover, the investigators will determine the effect of the RANTES receptor (CCR1/CCR5) antagonist Met- RANTES on the exacerbation of liver fibrosis elicited by TCE exposure in NOD.c3c4 mice. The expected outcome of these studies would be an improved understanding and detection of individual susceptibility to deleterious effects of TCE. Moreover, these studies would provide currently unavailable therapeutic strategies to counteract the exacerbation of fibrotic responses by TCE in individuals with autoimmunity.