Role of Bone Marrow-Derived Myeloid Cells in Alcohol Liver Disease

骨髓来源的髓样细胞在酒精性肝病中的作用

• 批准号: 8577602
• 负责人: Cynthia Ju
• 金额: $ 27.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8577602
• 关键词: Affect; Agonist; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Antibiotics; Antibodies; Bone Marrow; Cell surface; Cells; Characteristics; Chronic; Cirrhosis; Diet; Disease; Endotoxemia; Endotoxins; Ethanol; Ethanol Metabolism; Exhibits; Fibrosis; Harvest; Hepatic; Hepatocyte; Hybrids; ITGAM gene; Immune system; Infection; Infiltration; Inflammation Mediators; Inflammatory; Injury; Injury to Liver; Interleukin-6; Kupffer Cells; Lead; Leukocytes; Link; Lipopolysaccharides; Liver; Liver Fibrosis; Liver diseases; Matrix Metalloproteinases; Measures; Mediating; Microcirculation; Modeling; Molecular; Morphology; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; NF-kappa B; Natural regeneration; Oxidative Stress; PTGS2 gene; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Phenotype; Play; Population; Primary carcinoma of the liver cells; Recruitment Activity; Regulation; Research; Role; S100A8 gene; STAT1 gene; STAT3 gene; Severities; Signal Pathway; Signal Transduction; Simulate; Steatohepatitis; Sterility; Stimulus; Suppressor-Effector T-Lymphocytes; Tissues; Toll-like receptors; Vascular Endothelial Growth Factors; Work; Wound Healing; alcohol abuse therapy; alcohol exposure; base; effective therapy; feeding; inhibitor/antagonist; liver injury; liver transplantation; macrophage; monocyte; mouse model; neutralizing antibody; neutrophil; problem drinker; public health relevance; repaired; rifaximin; therapeutic development; therapeutic target; tissue repair; tumor

DESCRIPTION (provided by applicant): The only effective treatment for advanced alcohol liver disease (ALD) is liver transplantation. It is imperative to better understand the pathogenesi in order to advance therapeutic development. Evidence suggests that hepatic macrophages (Macs) play an important role; however research to date has not distinguished resident Macs, Kupffer cells (KCs), from infiltrating bone marrow-derived myeloid cells (BMMCs), which replenish KCs during pathological conditions. We detected BMMCs and distinguished them from KCs in the liver of mice treated with alcohol. We hypothesize that the BMMCs recruited into the liver during ALD assume different phenotypes and functions, depending on the microenvironment and severity of ALD. The Specific Aims of the proposed studies are: (Aim 1), investigate the mechanisms of hepatic BMMC accumulation as result of alcohol treatment. a) Livers from ethanol-fed mice will be harvested to examine message expression levels of IL-1b, IL-6, S100A8/A9, HSP72, and COX-2. b) The specific involvement of IL-1b and S100A8/A9 in hepatic accumulation of BMMCs will be investigated by using neutralizing antibodies and IL-1R-/- mice. c) The STAT3hep/- mice will be utilized to examine the role of hepatocyte-specific STAT3 signaling in BMMC accumulation in the liver after alcohol exposure. (Aim 2), Determine the phenotypes and functions of BMMCs in mild and advanced ALD. a) Chronic feeding of mice with 5% ethanol-containing Lieber-Decarli diet simulates mild ALD. Using this model, we will investigate the function of BMMCs in promoting the repair of alcohol-induced microcirculation disorder, and examine the roles of VEGF and MMPs in mediating such function. The CD11b-DTR mice and anti-Gr-1 antibody will be employed to deplete BMMCs in these studies. b) A hybrid model, in which mice are fed ad libitum with "Western diet" and intragastrically infused with ethanol, shares characteristics of alcoholic steatohepatitis (ASH) and liver fibrosis found in patients with advanced ALD. This model will be employed to examine the phenotype of BMMCs, and investigate their contribution to liver injury. (Aim 3), Dissect the molecular regulations of BMMC phenotypes in mild and advanced ALD. a) The systemic and hepatic levels of endotoxin and damage-associated molecular pattern (DAMP) molecules will be measured in the hybrid model of ALD. b) The contributions of endotoxin and DAMPs to pro-inflammatory activation of BMMCs and liver damage in the hybrid model will be investigated by administering mice with rifaximin antibiotic, and inhibitors of DAMPs. c) STAT3 activation and STAT1/NF-kB activation in BMMCs associated with mild ALD and ASH, respectively, will be investigated.

描述（由申请人提供）：晚期酒精性肝病（ALD）的唯一有效治疗方法是肝移植。为了推进治疗的发展，必须更好地了解发病机制。有证据表明肝巨噬细胞 (Mac) 发挥着重要作用；然而，迄今为止的研究尚未将常驻 Mac、库普弗细胞 (KC) 与浸润性骨髓源性骨髓细胞 (BMMC) 区分开来，后者在病理条件下补充 KC。我们检测了酒精处理小鼠肝脏中的 BMMC，并将其与 KC 区分开来。我们假设 ALD 期间招募到肝脏的 BMMC 具有不同的表型和功能，具体取决于 ALD 的微环境和严重程度。拟议研究的具体目标是：（目标 1），研究酒精治疗导致肝脏 BMMC 积累的机制。 a) 采集乙醇喂养小鼠的肝脏以检查 IL-1b、IL-6、S100A8/A9、HSP72 和 COX-2 的信息表达水平。 b) 将通过使用中和抗体和IL-1R-/-小鼠来研究IL-1b和S100A8/A9在BMMC的肝脏积聚中的具体参与。 c) STAT3hep/-小鼠将用于检查酒精暴露后肝细胞特异性STAT3信号在肝脏中BMMC积累中的作用。 （目标 2），确定轻度和晚期 ALD 中 BMMC 的表型和功能。 a) 长期用含 5% 乙醇的 Lieber-Decarli 饮食喂养小鼠模拟轻度 ALD。利用该模型，我们将研究BMMCs在促进酒精引起的微循环障碍修复中的功能，并研究VEGF和MMPs在介导这种功能中的作用。在这些研究中，CD11b-DTR 小鼠和抗 Gr-1 抗体将用于消耗 BMMC。 b) 一种混合模型，其中小鼠随意喂食“西方饮食”并灌胃注入乙醇，该模型具有酒精性脂肪性肝炎（ASH）和肝纤维化的特征 晚期 ALD 患者。该模型将用于检查 BMMC 的表型，并研究它们对肝损伤的贡献。 （目标 3），剖析轻度和晚期 ALD 中 BMMC 表型的分子调控。 a) 将在 ALD 混合模型中测量内毒素和损伤相关分子模式 (DAMP) 分子的全身和肝脏水平。 b) 将通过给小鼠施用利福昔明抗生素和 DAMP 抑制剂来研究混合模型中内毒素和 DAMP 对 BMMC 促炎激活和肝损伤的贡献。 c) 将分别研究与轻度 ALD 和 ASH 相关的 BMMC 中的 STAT3 激活和 STAT1/NF-kB 激活。