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) 包含多种病因，患者仅出现单纯脂肪变性 酒精性脂肪性肝炎 (ASH)、酒精性肝炎、肝硬化和导致肝功能衰竭的肝细胞癌。 研究探讨了 ALD 病理学对肝细胞的影响；然而，已知的信息有限 关于肥大细胞 (MC) 的作用以及 ALD 进展过程中与胆管细胞的相互作用。在不含酒精的情况下 脂肪肝病（NAFLD），衰老的胆管细胞表现出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。对于胆汁淤积患者和 NAFLD、MC 在衰老胆管周围的门静脉周围区域大量存在。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， NAFLD 表型已得到解决。干细胞因子 (SCF) 是胆汁淤积患者中上调的 SASP NAFLD 期间受损的胆管细胞增加。 SCF 与受体 c-Kit 相互作用（存在于 MC），而 SCF/c-Kit 是 MC 迁移的主要趋化剂途径。使用 Vivo- 抑制肝脏 SCF 吗啉治疗可降低 Mdr2-/- 小鼠的 MC 迁移和胆汁淤积性肝表型，并抑制 在体外，SCF 可阻止 MC 向受损胆管细胞迁移。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。研究有 证明了 MC 在 NAFLD 和非酒精性脂肪性肝炎期间的突出作用；然而，没有研究 已进行以了解 ALD 期间 MC 或与胆管细胞串扰的贡献。这 我们探索性研究的前提是建立在初步数据之上，这些数据表明 (i) MC 存在于周围 ASH 患者的胆管增加； (ii) 喂食乙醇 (EtOH) 的小鼠，血清 HA 和 SCF 增加； (iii) 套件W-sh 喂食 EtOH 的小鼠肝脏脂肪变性和炎症减少，并且 (iv) SCF 基因表达增加 胆管细胞，但不在喂食乙醇的小鼠的肝细胞中。基于这些发现，我们提出了小说 假设在 ALD 期间，受损的胆管细胞分泌增加的 SCF，招募 c-Kit 阳性 MC 肝脏通过与居民的旁分泌相互作用促进脂肪变性、导管反应、炎症和纤维化 肝细胞和 HA 信号传导增加。为了评估我们的假设，我们提出以下具体目标： 具体目标 1：证明 ALD 肝脏表型依赖于通过胆道 SCF 的 MC-HA 信号传导 和 MC c-Kit 交互；具体目标 2：在啮齿动物模型中测试 MC 稳定剂对 ALD 进展的影响。 我们将使用来自 ALD 的人体组织和对照以及由人体细胞构建的类器官来评估我们的目标（ 来自 co-I Burcin Ekser 博士的协助）以及慢性加暴食 EtOH 啮齿动物模型（Bin Gang-NIAAA） 模型）在合作者 Gianfranco Alpini 博士的协助下。这项研究既新颖又具有探索性， 有初步数据和可行实验的支持。如果成功，我们将为 MC 确定一个新角色 为 ALD 患者提供潜在的治疗生物标志物和治疗策略。