Ortega-Ribera Martí, Zhuang Yuan, Babuta Mrigya, Brezani Veronika, Joshi Radhika S, Zsengeller Zsuzsanna, Thevkar Nagesh Prashanth, Wang Yanbo, Bronson Roderick, Szabo Gyongyi
Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Department of Medicine, Division of Nephrology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Cell Mol Gastroenterol Hepatol. 2025;19(4):101446. doi: 10.1016/j.jcmgh.2024.101446. Epub 2024 Dec 20.
BACKGROUND & AIMS: Alcohol abuse is the most frequent precipitating factor of acute-on-chronic liver failure (ACLF). We aimed at developing an alcohol-induced ACLF model and dissecting its underlying molecular mechanisms.
ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis murine model. Liver, kidney, and brain tissues and behavior were assessed in mice. Livers from patients with sclerosing cholangitis with and without ACLF were also evaluated.
In advanced fibrosis induced by BDL, an alcohol binge induced features of ACLF, including significant liver damage, systemic inflammation (increased endotoxin and pro-inflammatory cytokines), and hepatocyte dysfunction compared with BDL alone. ACLF was associated with extrahepatic manifestations, including increased blood urea nitrogen and creatinine, impaired coagulation, and features of encephalopathy. We discovered significantly increased neutrophil count and neutrophil extracellular traps (NETs) in the liver, kidney, and brain in murine ACLF. Livers from ACLF mice showed increased pyroptosis (gasdermin D) and necroptosis (receptor-interacting protein kinase 3 [RIPK3]), when compared with BDL. In vitro, cell-free NETs were induced by alcohol and/or bile acids and triggered pyro-/necroptotic death in hepatocytes. NETosis, pyroptosis, and RIPK3 activation were validated in human livers with ACLF. Moreover, pharmacological inhibition of necroptosis with a RIPK3 inhibitor-ameliorated inflammation, NETs, and liver fibrosis, improving multi-organ ACLF pathophysiology.
Our novel ACLF model triggered by alcohol binge mimics key features of pathophysiology and multi-organ impairment in human ACLF. Our results indicate that neutrophil infiltration and NETs contribute to hepatocyte cell death via pyroptosis and necroptosis in ACLF, identifying RIPK3 as a potential therapeutic target.
酒精滥用是慢性肝衰竭急性发作（ACLF）最常见的诱发因素。我们旨在建立一种酒精诱导的ACLF模型，并剖析其潜在的分子机制。
在胆管结扎（BDL）肝纤维化小鼠模型中，通过单次暴饮酒精（5 g/kg）诱发ACLF。对小鼠的肝脏、肾脏、脑组织及行为进行评估。还对合并和未合并ACLF的硬化性胆管炎患者的肝脏进行了评估。
在BDL诱导的晚期肝纤维化模型中，与单纯BDL模型相比，单次暴饮酒精诱发了ACLF的特征，包括严重的肝损伤、全身炎症（内毒素和促炎细胞因子增加）以及肝细胞功能障碍。ACLF与肝外表现相关，包括血尿素氮和肌酐升高、凝血功能受损以及肝性脑病特征。我们发现，在小鼠ACLF模型中，肝脏、肾脏和脑组织中的中性粒细胞计数和中性粒细胞胞外陷阱（NETs）显著增加。与BDL模型相比，ACLF小鼠的肝脏中焦亡（gasdermin D）和坏死性凋亡（受体相互作用蛋白激酶3 [RIPK3]）增加。在体外，酒精和/或胆汁酸可诱导无细胞NETs形成，并触发肝细胞的焦亡/坏死性凋亡。在合并ACLF的人类肝脏中验证了NETosis、焦亡和RIPK3激活。此外，用RIPK3抑制剂对坏死性凋亡进行药理抑制可减轻炎症、NETs和肝纤维化，改善多器官ACLF的病理生理学。
我们建立的由暴饮酒精诱发的新型ACLF模型模拟了人类ACLF病理生理学和多器官损伤的关键特征。我们的结果表明，在ACLF中，中性粒细胞浸润和NETs通过焦亡和坏死性凋亡导致肝细胞死亡，确定RIPK3为潜在的治疗靶点。
Zotero 插件
