Mast Cell Regulation of Alcohol-Induced Liver Damage

肥大细胞对酒精引起的肝损伤的调节

• 批准号: 10539568
• 负责人: Heather L Francis
• 金额: $ 22.78万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-18 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539568
• 关键词: 3-Dimensional; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Alcoholic steatohepatitis; Alcohols; Area; Biliary; Cell Communication; Cell Degranulation; Cells; Chemotactic Factors; Cholangiocarcinoma; Cholestasis; Chronic; Chronic Hepatitis; Cirrhosis; Coupled; Cromolyn Sodium; Data; Development; Disease Progression; Disease model; Endothelial Cells; Ethanol; Etiology; Fatty Liver; Fibrosis; Gene Expression; Hepatic; Hepatic Stellate Cell; Hepatocyte; Histamine; Histamine Receptor; Human; In Vitro; Infiltration; Inflammation; Kupffer Cells; Link; Liver; Liver Failure; Liver diseases; Malignant neoplasm of liver; Mast Cell Stabilizer; Measures; Membrane; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Nonesterified Fatty Acids; Organoids; Outcome; Pathology; Pathway interactions; Patients; Phenotype; Primary carcinoma of the liver cells; Prognosis; Proto-Oncogene Protein c-kit; Reaction; Receptor Signaling; Regulation; Resolution; Risk Factors; Rodent Model; Role; Serum; Signal Transduction; Sodium; Stem Cell Factor; Testing; Therapeutic; Tissues; Up-Regulation; Work; alcohol effect; base; bile duct; blocking factor; cell motility; cholangiocyte; disease phenotype; experimental study; human tissue; liver inflammation; liver injury; mast cell; montelukast; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; paracrine; primary sclerosing cholangitis; receptor; recruit; senescence; simple steatosis; therapeutic biomarker; treatment strategy; tumor; western diet

Alcoholic liver injury (ALD) encompasses a vast array of etiologies and patients present with simple steatosis to alcoholic steatohepatitis (ASH), alcoholic hepatitis, cirrhosis, and hepatocellular carcinoma causing liver failure. Studies have examined the effects of ALD pathology on hepatocytes; however, limited information is known about the role of mast cells (MCs) and cross-talk with cholangiocytes during ALD progression. In non-alcoholic fatty liver disease (NAFLD), senescent cholangiocytes display a senescence-associated secretory phenotype (SASP), recruiting MCs to the liver where they interact with other liver cells. In patients with cholestasis and NAFLD, MCs are found in high numbers in the periportal area surrounding senescent bile ducts. Inhibition of MC-histamine (HA) ameliorates disease phenotypes. In MC-deficient mice (KitW-sh) subjected to Western Diet, there is resolution of NAFLD phenotypes. Stem cell factor (SCF) is a SASP upregulated in cholestatic patients and increased in damaged cholangiocytes during NAFLD. SCF interacts with the receptor, c-Kit, (present on MCs), and SCF/c-Kit is a prime chemoattractant pathway for MC migration. Inhibition of hepatic SCF using Vivo- Morpholino treatment decreases MC migration and cholestatic liver phenotypes in Mdr2-/- mice, and inhibition of SCF blocks MC migration toward damaged cholangiocytes, in vitro. In chronic hepatitis, MC degranulation and HA secretion are upregulated and increased SCF/c-Kit expression positively correlates to HA. Studies have demonstrated the prominent role for MCs during NAFLD and non-alcoholic steatohepatitis; however, no studies have been performed to understand the contribution of MCs or crosstalk with cholangiocytes during ALD. The premise of our exploratory study is built on preliminary data demonstrating that (i) MC presence surrounding bile ducts increases in ASH patients; (ii) in mice fed ethanol (EtOH), serum HA and SCF increase; (iii) KitW-sh mice fed EtOH have reduced hepatic steatosis and inflammation and (iv) SCF gene expression increases in cholangiocytes, but not in hepatocytes in mice fed EtOH. Based on these findings, we propose the novel hypothesis that during ALD, damaged cholangiocytes secrete increased SCF that recruits c-Kit-positive MCs to the liver promoting steatosis, ductular reaction, inflammation and fibrosis by paracrine interactions with resident liver cells and increased HA signaling. To evaluate our hypothesis, we propose the following specific aims: Specific aim 1: To demonstrate that ALD liver phenotypes are dependent on MC-HA signaling via biliary SCF and MC c-Kit interaction; and Specific aim 2: To test MC stabilizers on the progression of ALD in rodent models. We will evaluate our aims using human tissues from ALD and control and organoids built from human cells (with assistance from co-I, Dr. Burcin Ekser) along with chronic plus binge EtOH rodent models (Bin Gao-NIAAA model) with assistance from Dr. Gianfranco Alpini, collaborator. The study is both novel and exploratory, supported by preliminary data and feasible experiments. If successful, we will identify a new role for MCs along with potential therapeutic biomarkers and treatment strategies for those suffering from ALD.

酒精性肝损伤(ALD)包括多种病因，患者表现为单纯性脂肪变性 酒精性脂肪性肝炎(ASH)、酒精性肝炎、肝硬变和导致肝功能衰竭的肝细胞癌。 研究已经检验了ALD病理对肝细胞的影响；然而，所知的信息有限。 肥大细胞(MC)在ALD进展过程中的作用及与胆管细胞的相互作用。在非酒精饮料中 脂肪肝(NAFLD)，衰老的胆管细胞表现为衰老相关的分泌表型 (SASP)，将MC招募到肝脏，在那里它们与其他肝细胞相互作用。胆汁淤积和胆汁淤积患者 NAFLD、MC多见于老化胆管周围的汇管区。抑制 MC-组胺(HA)可改善疾病表型。在接受西方饮食的MC缺陷小鼠(KitW-sh)中， 有NAFLD表型的分辨。干细胞因子(SCF)是胆汁淤积症患者上调的一种SASP 在NAFLD过程中，受损的胆管细胞增加。SCF与受体c-Kit相互作用(存在于 MCS)，SCF/c-Kit是MC迁移的主要趋化途径。体内应用抑制肝干细胞因子的实验研究 吗啡治疗减少mdr2-/-小鼠的MC迁移和胆汁淤积性肝脏表型，并抑制 在体外，SCF阻止MC向受损的胆管细胞迁移。在慢性肝炎中，MC脱颗粒和 HA分泌上调，SCF/c-Kit表达增加与HA呈正相关。研究表明， MCs在NAFLD和非酒精性脂肪性肝炎中的显著作用；然而，没有研究 已进行的研究，以了解系膜细胞或与胆管细胞的串扰在ALD中的作用。这个 我们探索性研究的前提是初步数据表明：(I)MC存在周围 ASH患者胆管增加；(Ii)乙醇喂养的小鼠血清HA和SCF增加；(Iii)KitW-sh 饲喂乙醇的小鼠肝脏脂肪变性和炎症减轻，(Iv)SCF基因表达增加 在饲喂乙醇的小鼠中，胆管细胞呈阳性反应，而肝细胞则不呈阳性反应。基于这些发现，我们提出了这部小说 假设在ALD期间，受损的胆管细胞分泌的SCF增加，从而招募c-Kit阳性的MC 肝脏通过旁分泌与居民相互作用促进脂肪变性、导管反应、炎症和纤维化 肝细胞和增加的HA信号。为了评估我们的假设，我们提出了以下具体目标： 具体目标1：证明ALD肝脏的表型依赖于通过胆汁干细胞因子的MC-HA信号 和MC c-Kit相互作用；以及特定目标2：测试MC稳定剂对啮齿动物模型ALD进展的影响。 我们将使用来自ALD和对照的人类组织以及由人类细胞构建的有机类化合物来评估我们的目标(与 来自co-I，Burcin Ekser博士的帮助)以及慢性+暴饮暴食性啮齿动物模型(Bin Gao-niaa 模特)，合作者Gianfranco Alpini博士协助。这项研究既新颖又具有探索性， 有初步数据和可行性实验支持。如果成功，我们将确定MC的新角色 为ALD患者提供潜在的治疗生物标记物和治疗策略。