Mechanisms of fibrosis exacerbation by trichloroethylene in hepatic autoimmunity

三氯乙烯加重肝脏自身免疫纤维化的机制

• 批准号: 8898806
• 负责人: James P Luyendyk
• 金额: $ 19.16万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898806
• 关键词: Air; Applications Grants; Autoimmune Process; Autoimmune Responses; Autoimmunity; Biological Markers; Blood; Breathing; CCR1 gene; CCR5 gene; Carcinogens; Cholangitis; Collagen; Complement; Consumption; Deposition; Detection; Development; Dose; Enzymes; Epidemiologic Studies; Exposure to; Fibrosis; Gene Expression Profile; Genes; Goals; Hazardous Waste Sites; Health; Health Hazards; Hepatic; Human; Incidence; Individual; Kidney; Leukocytes; Link; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Mediating; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Non obese; Outcome Study; Pathogenesis; Pathway interactions; Patients; Predisposition; Prevalence; Primary biliary cirrhosis; Process; RANTES; RANTES receptor; RNA Sequences; Research; Research Personnel; Risk; Rodent; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Toxic effect; Trichloroethylene; United States; Urine; base; bile duct; chemokine; cytokine; diabetic; drinking water; effective therapy; environmental chemical exposure; exposed human population; gene environment interaction; human disease; impaired capacity; improved; injured; liver function; liver inflammation; liver injury; liver transplantation; meetings; mortality; mouse model; programs; response; superfund site; transcriptome sequencing; transcriptomics

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.

描述（由申请人提供）：人类接触三氯乙烯（TCE）仍然是美国和国外的紧迫关注。近年来，TCE的分类为人类致癌物进一步强调，需要完全定义TCE暴露于原因和加剧人类疾病的潜力。来自啮齿动物研究的强有力的实验证据将暴露于自身免疫性肝病的发展。这种联系通过流行病学研究证实，表明原发性胆汁肝硬化的患病率增加，这是一种自身免疫性肝病，靠近被TCE污染的危险废物地点。但是，对肝自身免疫的同时患者的TCE暴露风险的理解不足，并且没有对TCE影响自身免疫性肝脏疾病进展的机制的现有描述。长期目标是定义TCE加剧肝纤维化的机制，该机制持续的自身免疫性介导的肝损伤引起的肝纤维化。研究人员发现，小鼠暴露于与职业相关的TCE暴露水平显着增加了并存肝自免疫的小鼠的肝纤维化。这些研究的总体目的是确定TCE暴露对非肥胖糖尿病（NOD）的肝纤维化进展的影响。C3C4小鼠，C3C4小鼠，一种自身免疫性胆管炎的小鼠模型，并同时定义了NOD.C3C4小鼠对TCE代理症的自身免疫性的影响。他们的中心假设是，TCE暴露加剧了肝纤维化在肝自身免疫性中通过促进肝合成的肝纤维化，而TCE毒性因自身免疫肝病的TCE代谢而进一步加剧了TCE毒性。研究人员的赠款应用包括对TCE暴露对NOD.C3C4小鼠自身免疫性肝病发病机理的剂量和时间依赖性影响的全面分析。相度地，这些研究借鉴了调查团队的专业知识，以确定肝自身免疫对TCE代谢的影响。为了鉴定在肝自身免疫性中TCE暴露的机械生物标志物，拟议的研究利用RNA测序来鉴定肝脏和血液白细胞中TCE暴露差异失调的基因。此外，研究人员将确定rante受体（CCR1/CCR5）拮抗剂对TCE暴露在NOD.C3C4小鼠中引起的肝纤维化加剧的影响。这些研究的预期结果将是对个人对TCE有害影响的个人敏感性的理解和检测。此外，这些研究将提供目前无法获得的治疗策略，以抵消自身免疫患者TCE对纤维化反应的加剧。