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 本提案的目的是确定嗜中性粒细胞特异性NADPH氧化酶2（NOX 2）在酒精性 肝 疾病（ALD），并评估其作为治疗靶点的潜力。ALD影响超过1000万人， 在美国，几乎一半的肝硬化相关死亡病例都是由它引起的。了解其发病机制 ALD对于开发有效的治疗方法至关重要。肝脏中的神经递质积累是 对于ALD。有证据表明，中性粒细胞是酒精性肝脏病的关键因素。然而，更好地了解 需要在调节中性粒细胞功能中重要的分子途径来靶向这些细胞用于ALD 治疗最近发现，NADPH氧化酶（NOX）2的活性和表达水平， 活性氧（ROS）的来源，显着减少患者的中性粒细胞 晚期酒精性肝硬化或酒精性肝炎。虽然ROS与炎症有关， 越来越多的证据还表明，NOX 2衍生的ROS实际上在限制，而不是 促进炎症反应。考虑到NOX 2的矛盾作用，该提案旨在填补 关于NOX 2是否以及如何调节中性粒细胞功能的知识空白。 我们的初步数据表明，具有嗜中性粒细胞特异性NOX 2缺失的小鼠发生恶化， 慢性加酒精治疗后肝损伤和长期炎症。NOX 2缺陷型中性粒细胞 比WT-中性粒细胞释放更高水平的IL-1 β。这些发现共同导致了我们的假设， 嗜中性粒细胞特异性NOX 2在限制炎症和促进炎症消退中起着关键作用。 ALD期间的炎症。我们提出了三个具体目标：（1）阐明解释 在ALD过程中，NOX 2缺陷型中性粒细胞产生的IL-1 β增加，（2）研究中性粒细胞在ALD中的作用， 特异性NOX 2在ALD期间炎症消退中的作用，（3）评估靶向中性粒细胞的潜力- 特异性NOX 2来治疗ALD。