Role of neutrophil-specific NOX2 in alcohol-induced liver injury

中性粒细胞特异性NOX2在酒精性肝损伤中的作用

• 批准号: 10621545
• 负责人: Cynthia Ju
• 金额: $ 43.24万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621545
• 关键词: Accounting; Adoptive Transfer; Adrenal Cortex Hormones; Affect; Agonist; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcohols; Attenuated; Cells; Cessation of life; Chronic; Data; Defect; Development; Disease; Ethanol; Exhibits; Goals; Impairment; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Liver; Liver Cirrhosis; Macrophage; Mitochondria; Modeling; Molecular; Mus; NADPH Oxidase; National Institute on Alcohol Abuse and Alcoholism; Pathogenesis; Pathway interactions; Patients; Pentoxifylline; Persons; Pharmacologic Substance; Phase; Phenotype; Play; Predisposition; Production; Reactive Oxygen Species; Resolution; Role; Serine Protease; Source; effective therapy; inflammatory marker; insight; liver inflammation; liver injury; liver transplantation; molecular marker; neutrophil; novel; therapeutic development; therapeutic target

PROJECT SUMMARY The goal of this proposal is to define the role of neutrophil-specific NADPH oxidase 2 (NOX2) in alcoholic liver disease(ALD) and to evaluate its potential as a therapeutic target. ALD affectsmore than 10 million people in the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. Understanding the pathogenesis of ALD is imperative for the development of effective therapies. Neutrophil accumulation in the liver is a hallmark for ALD. Evidence suggests that neutrophils are a key contributor to ALD. However, better understanding of molecular pathways important in regulating neutrophil functions is required to target these cells for ALD treatment. It is recently revealed that the activity and expression levels of NADPH oxidase (NOX)2, a major source of reactive oxygen species (ROS), were dramatically reduced in neutrophils from patients with advanced alcoholic cirrhosis or alcoholic hepatitis. Although ROS has been associated with inflammation, mounting evidence also suggests that NOX2-derived ROS actually plays a critical role in limiting, rather than promoting, inflammatory responses. Given the paradoxical role of NOX2, this proposal aims to fill the knowledge gaps regarding whether and how NOX2 regulates neutrophil functions. Our preliminary data demonstrate that mice with neutrophil-specific deletion of NOX2 develop exacerbated liver injury and prolonged inflammation after chronic plus binge ethanol treatment. NOX2-deficient neutrophils release much higher levels of IL-1 than WT-neutrophils. Together these findings led to our hypothesis that neutrophil-specific NOX2 plays a critical role in limiting inflammation and promoting resolution of inflammation during ALD. We propose three Specific Aims to (1) elucidate the mechanism accounting for increased IL-1 production by NOX2-deficient neutrophils during ALD, (2) investigate the role of neutrophil- specific NOX2 in the resolution of inflammation during ALD, (3) evaluate the potential of targeting neutrophil- specific NOX2 to treat ALD.

项目摘要 该提议的目的是定义酒精中嗜中性粒细胞特异性NADPH氧化酶2（NOX2）的作用 肝 疾病（ALD）并评估其作为治疗靶标的潜力。 ALD影响超过1000万人 美国，占肝硬化相关死亡的近一半。了解 ALD对于开发有效疗法是必不可少的。中性粒细胞在肝脏中的积累是一个标志 对于Ald。有证据表明，中性粒细胞是ALD的关键因素。但是，更好地理解 对于确定嗜中性粒细胞功能很重要的分子途径才能将这些细胞靶向ALD 治疗。最近揭示了NADPH氧化物（NOX）2的活性和表达水平，一个主要 活性氧（ROS）的来源在中性粒细胞中大幅降低 尽管ROS与炎症有关，但 越来越多的证据也表明，NOX2衍生的ROS实际上在限制中起着至关重要的作用 促进炎症反应。鉴于NOX2的矛盾作用，该提议旨在填补 关于NOX2是否调节中性粒细胞功能的知识差距。 我们的初步数据表明，NOX2的中性粒细胞特异性缺失的小鼠发展了 肝损伤和慢性乙醇治疗后的长时间感染。 NOX2缺乏性中性粒细胞 释放比WT-中性基质更高的IL-1水平。这些发现共同提出了我们的假设 中性粒细胞特异性NOX2在限制注入和促进分辨率方面起着至关重要的作用 ALD期间的炎症。我们提出了三个具体目标，以（1）阐明该机制 在ALD期间，NOX2缺乏性中性粒细胞的IL-1产生增加，（2）研究中性粒细胞的作用 特定的NOX2在ALD期间的炎症解决中，（3）评估靶向嗜中性粒细胞的潜力 特定的NOX2治疗ALD。