Interactions between neutrophils and cholangiocytes in alcoholic hepatitis

酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用

• 批准号: 10617893
• 负责人: MICHAEL H NATHANSON
• 金额: $ 16.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-25 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617893
• 关键词: 2019-nCoV; Affect; Alcohol consumption; Alcoholic Hepatitis; Alcoholic steatohepatitis; Alcohols; American; Autopsy; Binding; Biopsy; COVID-19; COVID-19 complications; COVID-19 impact; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; Cardiopulmonary; Cell Death; Cells; Cessation of life; Characteristics; Clinical; Complication; Contracts; Disease; Endotoxins; Environment; Event; Exhibits; Exposure to; Fatty Liver; Goals; Health system; Hepatitis; Hepatocellular Damage; Hepatocyte; Human; Individual; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Institution; Laboratories; Lead; Leukocytes; Liver; Liver Failure; Liver diseases; Lymphocyte; Mediating; Metabolic; Morbidity - disease rate; Necrosis; Outcome; Pathologic; Pathway interactions; Patients; Population; Reporting; Risk Factors; SARS-CoV-2 infection; Signal Pathway; Signal Transduction; Steatohepatitis; Testing; Transaminases; Tumor-infiltrating immune cells; United States National Institutes of Health; Viral; Virus; Writing; alcohol exposure; base; cell type; cholangiocyte; cytokine; cytokine release syndrome; economic impact; experience; falls; hepatocyte injury; liver inflammation; liver injury; mortality; neutrophil; novel; response; synergism; therapeutic target; thrombogenesis

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, began in late fall of 2019 and now has spread throughout most of the world. As of this writing, there are over 500 million cases worldwide, including over 80 million cases in the US, approximately 987,000 of whom have died from the infection. We analyzed the first 1,827 patients hospitalized with COVID-19 at our institution and found that the liver is usually involved – AST is elevated in over 80% of our patients, while ALT is elevated in over 60% - and infected patients with elevated transaminases are nearly twice as likely to die. Our subsequent clinical-pathological study furthermore showed that most patients who died exhibited hepatic steatosis and inflammation. In addition, it is now appreciated that pre-existing alcohol-associated liver disease (AALD), which typically includes steatohepatitis, is an independent risk factor that increases mortality more than two-fold. Although most patients who die of COVID-19 do not have liver failure, these findings instead raise the possibility that the steatohepatitis that occurs in AALD results in the pro-inflammatory, thrombogenic state responsible for the cardiopulmonary complications that usually cause a more severe and often fatal course. The goal of this project is to determine whether and how alcoholic steatohepatitis synergizes with SARS-CoV-2 infection to exacerbate the pro-inflammatory state associated with a worse outcome, with the ultimate aim of determining therapeutic targets to block this synergy. The specific hypothesis to be tested is that SARS-CoV-2 infection in the setting of AALD causes pathological white blood cell (WBC)-hepatocyte interactions that result in release of inflammatory cytokines markedly exceeding what is caused by SARS-CoV-2 infection or AALD alone. In order to test this, we will ascertain whether white blood cells (WBCs) are responsible for COVID-19 liver damage, and if so, determine which type of WBC is responsible. We also will determine whether the SARS-CoV-2 virus causes direct cytopathic damage to hepatocytes, and whether the hepatocytes are more susceptible to damage if they have steatosis or have been exposed to alcohol. This hypothesis will be tested through three specific aims: (1) We will determine whether and which type of WBCs from COVID-19-infected patients interact with human hepatocytes; (2) We will determine whether steatosis or other intracellular factors make hepatocytes susceptible to damage from the SARS-CoV-2 virus and/or potentiate cytokine release; and (3) Based on these results, we will identify the signaling pathways activated in hepatocytes by WBCs and by direct viral entry that result in hepatocellular damage and cytokine release in COVID-19 infection. This project may have a broad impact on our understanding of how alcohol consumption affects COVID-19 outcomes by determining the mechanism for increased mortality in COVID-19 patients with AALD. The PI is an experienced liver cell biologist and a practicing hepatologist, his primary collaborator is a hepatitis virologist with specific SARS-CoV-2 expertise, and they will take advantage of Yale's NIH-sponsored Liver Center, so the environment is uniquely suited to support this project as well.

由SARS-COV-2病毒引起的COVID-19大流行，从2019年末开始，现在已经扩散 在整个世界大部分地区。截至撰写本文时，全球有超过5亿个案件，包括80多个案件 在美国，大约有987,000例死于感染的案件。我们分析了第一个 1,827名患者在我们机构的Covid-19住院，发现肝脏通常涉及 - AST是 超过80％的患者升高，而在60％以上的ALT升高 - 感染的患者升高 转氨酶死亡的可能性几乎是两倍。我们随后的临床病理研究还显示 大多数死亡的患者暴露了肝脂肪变性和炎症。此外，现在感谢 通常包括脂肪性肝炎的酒精相关肝病（AALD）是独立的 增加死亡率超过两个以上的危险因素。虽然大多数死于Covid-19的患者没有 肝脏衰竭，这些发现提出了ALD中发生的脂肪性肝炎导致脂肪性肝炎导致的可能性 促炎性，血栓形成状态，负责心肺并发症，通常引起 更严重，经常致命的病程。该项目的目的是确定是否酗酒 脂肪性肝炎与SARS-COV-2感染协同作用，以加剧与 更糟糕的结果，最终的目的是确定治疗靶点以阻止这种协同作用。具体 要检验的假设是AALD环境中SARS-COV-2感染引起病理白细胞 （WBC） - 肝细胞相互作用，导致炎症细胞因子释放明显超过什么 由SARS-COV-2感染或仅AALD引起。为了测试这一点，我们将确定是否白细胞 （WBC）负责19009年肝损害，如果是，请确定哪种类型的WBC负责。我们 还将确定SARS-COV-2病毒是否对肝细胞造成直接细胞病毒损伤，以及是否会导致 如果肝细胞患有脂肪变性或暴露于酒精，则更容易受到损害。这 假设将通过三个特定目的进行检验：（1）我们将确定是否以及哪种类型的WBC 来自共同19感染的患者与人肝细胞相互作用； （2）我们将确定是脂肪变性还是 其他细胞内因子使肝细胞容易受到SARS-COV-2病毒和/或电势损害的损害 细胞因子释放； （3）基于这些结果，我们将确定在肝细胞中激活的信号通路 通过WBC和直接病毒进入，导致肝细胞损伤和COVID-19中的细胞因子释放 感染。该项目可能对我们对饮酒的理解产生广泛的影响 Covid-19结局通过确定COVID-19患者AALD患者死亡率增加的机制。 PI是一位经验丰富的肝细胞生物学家，也是一名实用的肝病学家，他的主要合作者是肝炎 具有特定SARS-COV-2专业知识的病毒学家，他们将利用耶鲁大学NIH赞助的肝脏 中心，因此环境也非常适合支持该项目。