Mechanisms of synergistic regulation of biliary inflammation and fibrosis

胆道炎症和纤维化的协同调节机制

基本信息

批准号：
10554318
负责人：
Heather L Francis
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10554318
关键词：
Alcohols Bile duct carcinoma Bile fluid Biliary Breeding Cell Line Cells Chemotactic Factors Cholangiocarcinoma Cholestasis Cicatrix Data Development Disease Disease Progression Event Fibrosis Hepatic Hepatic Stellate Cell Hepatitis Viruses Histamine Histidine Decarboxylase Hospitalization In Vitro Infiltration Inflammation Interleukins Intrahepatic bile duct Knockout Mice Kupffer Cells Link Liver Liver Fibrosis Liver diseases Mediating Mediator Medical Mission Modeling Morbidity - disease rate Mus Nuclear Receptors Organ Organ Transplantation Pathology Patients Phenotype Predisposition Proliferating Publishing Reaction Regulation Research Risk Rodent Model Role Signal Transduction Stem Cell Factor Therapeutic Toxin Transforming Growth Factors Transplantation Veterans Wild Type Mouse Work bile duct biliary tract cell motility cholangiocyte chronic liver disease effective therapy immune cell infiltrate in vivo Model interest liver injury mast cell migration mortality non-alcoholic fatty liver disease novel therapeutics primary sclerosing cholangitis programs recruit senescence stem-like cell

项目摘要

The risk of liver diseases due to alcohol and toxin abuse and hepatitis viruses in US Veterans is increasingly high and is one of the most common reasons for hospitalization and mortality. Hepatic fibrotic disease represents one of the largest groups of disorders for which there is no effective therapy and thus denotes a major unmet medical need. Often the only option for patients with liver fibrosis is organ transplantation. Chronic liver diseases include cholangiopathies that target cholangiocytes such as Primary Sclerosing Cholangitis (PSC) which is characterized by biliary proliferation, inflammation and progressive fibrosis. Unrestrained cholangiocyte proliferation can develop into cancer of the bile ducts (i.e., cholangiocarcinoma, CCA) and patients with PSC are more susceptible to development of CCA. Further, cholangiocytes display a senescent phenotype during PSC which may contribute to inflammation and further influence hepatic fibrosis by activating hepatic stellate cells (HSCs). It has been shown that damaged cholangiocytes secrete senescence-associated secretory phenotypes (SASP). Mast cells (MCs) are important in mediating numerous pathologies including liver diseases, but are found at very low numbers in normal, homeostatic livers. Infiltrating hepatic MCs are found near damaged intrahepatic bile ducts and activated HSCs. In unpublished data, we have found that damaged, senescent cholangiocytes induce MC migration during non-alcoholic fatty liver disease. Further, senescent cholangiocytes secrete factors like stem cell factor (SCF) and interleukins that are known to be chemoattractants for MCs, inducing migration. Following migration and activation, MCs release mediators including large amounts of histamine that stimulates cholangiocyte proliferation and fibrosis. The rationale for our proposal is built upon previously published data from our lab and others showing that MC infiltration increases in PSC and CCA patients along with rodent models of liver damage, and MC infiltration positively correlates with increased fibrosis. Additionally, normal wild-type mice (typically very few hepatic MCs) injected with cultured MCs display increased biliary damage, inflammation and hepatic fibrosis, all of which are key features of PSC. Using a model of PSC (Mdr2-/- mice) we generated a double knockout mouse (DKO) by breeding Mdr2-/- with mice lacking histidine decarboxylase (HDC-/-). DKO mice (few to no MCs) have decreased biliary damage, inflammation and hepatic fibrosis. Further, upon reintroduction of MCs into DKO mice, we find a striking increase in damage and fibrosis that mimics Mdr2-/- mice, which was reversed when MCs lacking TGF-β1 signaling were used demonstrating a key role for MCs in PSC. Finally, inhibition of MC-derived histamine decreases biliary damage and hepatic fibrosis in models of cholestatic liver injury, PSC and CCA suggesting that modulation of MCs mediators may prove therapeutic. We propose the working hypothesis that senescent cholangiocytes induce MC migration during PSC and modulation of MC-derived TGF-β1 or FXR regulates ductular reaction and hepatic fibrosis via biliary senescence. We propose the following specific aims (SAs): (SA1) Senescent cholangiocytes recruit MCs to the liver by secretion of specific SASPs during PSC; (SA2) MCs promote liver and biliary damage, inflammation and hepatic fibrosis resembling PSC in normal mice or mice lacking MCs; and (SA3) MCs exacerbate biliary damage and hepatic fibrosis during PSC via cellular crosstalk between histamine, TGF-β1 and FXR.

美国退伍军人因酗酒、滥用毒素和肝炎病毒而患肝脏疾病的风险日益增加高，是肝纤维化疾病住院和死亡的最常见原因之一。最大的一组疾病，没有有效的治疗方法，因此表示一个重大的未满足的问题肝纤维化患者的医疗需求通常是器官移植。包括针对胆管细胞的胆管病，例如原发性硬化性胆管炎（PSC）其特征是胆管增殖、炎症和进行性纤维化。增殖可发展为胆管癌（即胆管癌，CCA），PSC 患者此外，PSC 期间胆管细胞表现出衰老表型。这可能会导致炎症，并通过激活肝星状细胞进一步影响肝纤维化（HSC）已被证明受损的胆管细胞会分泌衰老相关的分泌表型。 (SASP)。肥大细胞 (MC) 在介导包括肝脏疾病在内的多种病理过程中发挥着重要作用，但在正常的稳态肝脏中发现的数量非常少，在受损的肝脏附近发现了浸润性 MC。在未发表的数据中，我们发现肝内胆管和活化的HSCs受损、衰老。胆管细胞在非酒精性脂肪肝疾病期间诱导 MC 迁移。分泌干细胞因子 (SCF) 和白细胞介素等因子，这些因子已知是 MC 的化学引诱剂，诱导迁移。迁移和激活后，MC 会释放大量介质。刺激胆管细胞增殖和纤维化的组胺我们提议的基本原理是建立在这种基础上的。我们实验室和其他实验室之前发布的数据显示，PSC 和 CCA 患者中 MC 浸润增加与肝损伤的啮齿动物模型一样，MC 浸润与纤维化增加呈正相关。此外，注射培养 MC 的正常野生型小鼠（通常很少有肝脏 MC）表现出增加胆道损伤、炎症和肝纤维化，所有这些都是 PSC 使用 PSC 模型的关键特征。（Mdr2-/- 小鼠）我们通过将 Mdr2-/- 与缺乏组氨酸的小鼠交配产生了双敲除小鼠 (DKO) 脱羧酶 (HDC-/-) 小鼠（很少或没有 MC）减少了胆道损伤、炎症和肝脏。此外，将 MC 重新引入 DKO 小鼠后，我们发现损伤和纤维化显着增加。模仿 Mdr2-/- 小鼠，当使用缺乏 TGF-β1 信号传导的 MC 时，结果发生逆转，证明了最后，抑制 MC 衍生的组胺可减少胆道损伤和肝脏损伤。胆汁淤积性肝损伤、PSC 和 CCA 模型中的纤维化表明 MCs 介质的调节可能我们提出了衰老胆管细胞诱导 MC 的工作假设。 PSC 期间的迁移和 MC 衍生的 TGF-β1 或 FXR 的调节可调节导管反应和我们提出以下具体目标（SA）：（SA1）衰老。胆管细胞在 PSC 期间通过分泌特定的 SASP 将 MC 募集到肝脏 (SA2) MC 促进肝脏和正常小鼠或缺乏 MC 的小鼠中胆道损伤、炎症和肝纤维化重新组装 PSC； (SA3) MC 在 PSC 过程中通过组胺、 TGF-β1 和 FXR。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Heterogeneity of Hepatic Stellate Cells in Fibrogenesis of the Liver: Insights from Single-Cell Transcriptomic Analysis in Liver Injury.

DOI：
10.3390/cells10082129
发表时间：
2021-08-19
期刊：
Cells
影响因子：
6
作者：
Zhang W;Conway SJ;Liu Y;Snider P;Chen H;Gao H;Liu Y;Isidan K;Lopez KJ;Campana G;Li P;Ekser B;Francis H;Shou W;Kubal C
通讯作者：
Kubal C

Fructose Promotion of Intestinal and Liver Injury: A Sugar by Any Other Name That Isn't So Sweet.