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

项目总结 这项提议的目的是确定中性粒细胞特异性NADPH氧化酶2(NOX2)在酒精中毒中的作用 肝脏 评估其作为治疗靶点的潜力。阿尔茨海默病影响了1000多万人 在美国，占与肝硬变相关的死亡人数的近一半。了解黄斑狼疮的发病机制 ALD对于开发有效的治疗方法是必不可少的。中性粒细胞聚集在肝脏是一个标志。 对于ALD来说。有证据表明，中性粒细胞是ALD的关键贡献者。然而，更好地理解 ALD靶向这些细胞需要调节中性粒细胞功能的重要分子途径 治疗。最近发现，NADPH氧化酶(NOX)2的活性和表达水平是一种主要的 患者中性粒细胞中活性氧物种(ROS)的来源显著减少 晚期酒精性肝硬变或酒精性肝炎。尽管ROS与炎症有关， 越来越多的证据也表明，NOX2衍生的ROS实际上在限制、而不是 促进炎症反应。考虑到NOX2的矛盾角色，这项提议旨在填补 关于NOX2是否以及如何调节中性粒细胞功能的知识空白。 我们的初步数据显示，中性粒细胞特异性缺失NOX2的小鼠发生恶化 慢性加酗酒治疗后的肝脏损伤和长期炎症。NOX2缺乏的中性粒细胞 释放比WT-中性粒细胞高得多的IL-1水平。综合起来，这些发现导致了我们的假设 中性粒细胞特异性NOX2在抑制炎症和促进消退中发挥关键作用 ALD期间的炎症反应。我们提出了三个具体的目标：(1)阐明 NOX2缺陷的中性粒细胞在酒精性肝病中增加IL-1的产生，(2)研究中性粒细胞- 特异性NOX2在ALD炎症消退中的作用，(3)评价靶向中性粒细胞的潜能。 治疗ALD的特异性NOX2。

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.