Mechanisms of Alcoholic Liver Disease

酒精性肝病的机制

• 批准号: 7963847
• 负责人: bin gao
• 金额: $ 64.96万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7963847
• 关键词: Acceleration; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Apoptosis; Attenuated; Cell Cycle Arrest; Cells; Cytokine Inducible SH2-Containing Protein; Endocannabinoids; Endothelial Cells; Ethanol; Fatty Liver; Fibrosis; Goals; Hepatitis; Hepatocyte; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interferon Type II; Interleukin-10; Interleukin-6; Knockout Mice; Laboratories; Ligands; Liver; Liver Fibrosis; Liver diseases; Mediating; Modeling; Molecular; Mus; Myelogenous; NK Cell Activation; National Institute on Alcohol Abuse and Alcoholism; Natural Killer Cells; Oxidative Stress; Patients; Play; Poly I-C; Production; Resistance; Role; STAT1 protein; Signal Transduction; Signaling Protein; Stat3 protein; System; T-Lymphocyte; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral hepatitis; Wild Type Mouse; bile duct; cell killing; chronic alcohol ingestion; cytotoxicity; feeding; human TGFB1 protein; liver transplantation; macrophage; member; neutralizing antibody; neutrophil; non-alcoholic fatty liver; novel; prevent; problem drinker; therapeutic target

Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on (1) the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation; (2) the role of natural killer (NK) cells in alcoholic liver fibrosis. IL-6/IL-10/STAT3 in alcoholic liver disease We have previously demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). Immunohistochemistry analyses show that phosphorylated STAT3 (STAT3 activation) are detected in hepatocytes, sinusoidal endothelial cells, bile duct-like cells, and inflammatory cells (macrophages, neutrophils etc) in human alcoholic cirrhotic livers. By using liver-specific and macrophage/neutrophil-specific STAT3 knockout mice, we have demonstrated that hepatocyte STAT3 inhibits alcoholic fatty liver but promotes liver inflammation, while myeloid STAT3 inhibits alcoholic liver inflammation. Interestingly, IL-6-deficient mice are more susceptible to alcohol-induced fatty liver and liver injury (hepatocyte apoptosis), while hepatocyte-specific STAT3 knock out mice are only more susceptible to alcohol-induced hepatic steatosis and have similar hepatocyte apoptosis after alcohol feeding compared to wild type mice. This suggests that the hepatoprotection of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. Our recent studies suggest that endothelial cell STAT3 plays an important role in preventing alcohol-induced liver injury and inflammation. Compared to wild type mice, endothelial cell specific STAT3 knock out mice are more susceptible to alcohol-induced liver inflammation, hepatocyte and endothelial cell apoptosis. Currently, we are also exploring the role of IL-10 in alcoholic liver disease. Abrogation of the anti-fibrotic effect of NK/IFN-gamma contributes to ethanol acceleration of liver fibrosis Chronic alcohol drinking accelerates liver fibrosis in patients with viral hepatitis that cannot be fully explained by ethanol-enhanced liver damage. Recently, we identified a novel mechanism by which alcohol accelerates liver fibrosis: inhibition of the antifibrotic effects of natural killer (NK) cells and interferon-gamma (IFN-gamma). CCl(4) treatment induced greater fibrosis and less apoptosis of HSCs in ethanol-fed mice compared with pair-fed mice. Polyinosinic-polycytidylic acid (Poly I:C) or IFN-gamma treatment inhibited liver fibrosis in pair-fed but not in ethanol-fed mice. Poly I:C activation of NK cell cytotoxicity against HSCs was attenuated in ethanol-fed mice compared with pair-fed mice, which was due to reduced natural killer group 2 member D (NKG2D), tumor necrosis factor-related apoptosis-inducing ligand, and IFN-gamma expression on NK cells from ethanol-fed mice. In vitro, HSCs from ethanol-fed mice were resistant to IFN-gamma-induced cell cycle arrest and apoptosis compared with pair-fed mice. Such resistance was due to diminished IFN-gamma activation of signal transducer and activator of transcription 1 (STAT1) in HSCs from ethanol-fed mice caused by the induction of suppressors of cytokine signaling proteins and the production of oxidative stress. Finally, HSCs from ethanol-fed mice were resistant to NK cell killing, which can be reversed by transforming growth factor-beta1 (TGF-beta1) neutralizing antibody. In conclusion: chronic ethanol consumption attenuates the antifibrotic effects of NK/IFN-gamma/STAT1 in the liver, representing new and different therapeutic targets with which to treat alcoholic liver fibrosis. In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.

我们的实验室一直在积极研究酒精性肝病的分子机制，重点是（1）（1）白介素6（IL-6）和IL-10及其下游信号STAT3在酒精脂肪肝和肝脏炎症中的作用； （2）天然杀伤（NK）细胞在酒精性肝纤维化中的作用。 酒精性肝病中的IL-6/IL-10/STAT3 我们以前已经证明，在几种酒精性肝损伤，非酒精性脂肪肝病，脂肪肝移植和T细胞肝炎的鼠模型中，IL-6在保护肝损伤方面起着重要作用。据信，IL-6的作用是通过信号传感器的激活和转录3的激活因子（STAT3）介导的。免疫组织化学分析表明，在人类酒精cirrhotic肝脏中，在肝细胞，正弦核心内皮细胞，胆汁导管样细胞和炎性细胞（巨噬细胞，中性粒细胞等）中检测到磷酸化的Stat3（Stat3激活）。通过使用肝脏特异性和巨噬细胞/中性粒细胞特异性STAT3敲除小鼠，我们证明肝细胞Stat3抑制了酒精脂肪肝肝，但会促进肝炎炎症，而髓样STAT3抑制了酒精性肝炎症。 有趣的是，IL-6缺陷型小鼠更容易受到酒精诱导的脂肪肝和肝损伤（肝细胞凋亡），而肝细胞特异性的STAT3敲除小鼠只有与酒精诱导的肝脂肪变性更容易受到肝脂肪细胞的饮酒相比，与野生型的肝细胞喂养相似。这表明，IL-6在酒精肝损伤中的肝脏保护可以通过激活肝细胞中STAT3独立信号的激活，非正质细胞中Stat3的激活或两者介导。我们最近的研究表明，内皮细胞STAT3在防止酒精引起的肝损伤和炎症方面起着重要作用。与野生型小鼠相比，内皮细胞特异性STAT3敲除小鼠更容易受到酒精诱导的肝脏炎症，肝细胞和内皮细胞凋亡的影响。 目前，我们还在探索IL-10在酒精性肝病中的作用。 NK/IFN-GAMMA抗纤维化作用的废除有助于肝纤维化的乙醇加速度 慢性酒精饮酒会加速病毒性肝炎患者的肝纤维化，这无法完全通过乙醇增强肝损伤来解释。最近，我们确定了一种新型机制，通过该机制加速肝纤维化：抑制天然杀手（NK）细胞和干扰素 - γ（IFN-GAMMA）的抗纤维化作用。 与配对小鼠相比，CCL（4）治疗诱导乙醇喂养小鼠中HSC的纤维化较大，HSC凋亡较少。聚激素多胞酸酸（Poly I：C）或IFN-GAMMA治疗抑制了配对喂养的肝纤维化，但在乙醇喂养的小鼠中抑制了肝纤维化。与成对的小鼠相比，乙醇喂养的小鼠对NK细胞细胞毒性的poly I：C激活减弱，这是由于自然杀伤力降低了2组成员D（NKG2D），肿瘤坏死因子因子因子与凋亡的凋亡诱导的配体诱导NK-GAMMA，以及对NK-GAMMA的表达，以及对IFN-GAMMA的表达，以及对乙醇元素的表达。在体外，与配对小鼠相比，来自乙醇喂养的小鼠的HSC对IFN-γ诱导的细胞周期停滞和凋亡具有抗性。这种耐药性是由于信号转换剂的IFN-γ激活减少，以及来自乙醇喂养小鼠的HSC中的转录1（STAT1）激活，这是由于诱导细胞因子信号蛋白抑制和产生氧化应激引起的。最后，来自乙醇喂养的小鼠的HSC对NK细胞杀伤具有抵抗力，可以通过转化中和抗体的生长因子-BETA1（TGF-BETA1）来逆转。总之：慢性乙醇消耗减轻了NK/IFN-GAMMA/STAT1在肝脏中的抗纤维化作用，代表了治疗酒精性肝纤维化的新的和不同的治疗靶标。 此外，我们还与DRS合作。 NIAAA的乔治·库诺斯（George Kunos）和帕尔·帕切（Pal Pacher）研究内源性大麻素系统在酒精性肝病中的作用。