RC#2: Macrophage Oxidant Stress and Dysfunction

埃默里酒精和肺生物学中心在多项研究中证明，长期酗酒 导致以前未被认识到的肺氧化应激，导致多种细胞类型的功能障碍。 在临床和动物研究中，慢性酒精摄入会耗尽肺泡衬里液体谷胱甘肽(GSH)，a 关键抗氧化剂，降低-80%，氧化还原电位35-50 mV。在项目2中，目标是澄清 慢性酒精摄入抑制肺泡巨噬细胞(AM)的离散机制 成熟和免疫功能，并使个人容易受到严重的肺部感染，如 细菌性肺炎和肺结核。该中心第一阶段的研究表明， 酒精诱导的氧化应激损害AM分化和必需受体的表面表达 以促进吞噬和呼吸爆发。这些精神错乱可以通过口服补充剂来治愈。 谷胱甘肽前体。此外，研究中心的研究人员证明，酒精诱导的氧化应激 增加转化生长因子(Topp^)的表达。因为，转化生长因子(3i)可以增加表达 NADPH氧化酶的活性和NADPH氧化酶产生的ROS能上调TGFpi，我们推测 慢性酒精摄入上调TGFfr和NADPH氧化酶的前馈环路，促进 慢性ROS的产生，导致AM终末分化受损。因此，受损的终端 分化导致AM质膜表达减少所需的受体 触发吞噬和呼吸爆发，从而使肺泡腔容易受到 感染。在目标1-3中，将使用慢性乙醇摄取的小鼠模型来检查 乙醇诱导的氧化应激与NADPH氧化酶活性、TGFpi上调、 AM的终末分化受损和细胞功能障碍。埃默里酒的独特力量 中心通过与AIM 4中的临床核心密切合作来突出显示，在那里，患有或 没有长期酗酒史的人将被招募。在基线支气管肺泡灌洗后 AM检查，受试者将随机接受S腺苷蛋氨酸或安慰剂治疗 以确定SAM是否能减轻酒精引起的AM的排列紊乱。这些研究有可能 确定酒精中毒者肺炎和肺损伤的新机制和治疗方法。

The Emory Alcohol and Lung Biology Center has demonstrated in multiple studies that chronic alcohol abuse causes a previously unrecognized pulmonary oxidant stress that generates dysfunction of multiple cell types. In clinical and animal studies, chronic alcohol ingestion depletes the alveolar lining fluid glutathione (GSH), a critical antioxidant, by -80% and oxidizes the redox potential by 35-50 mV. In Project 2, the goal is to clarify the discrete mechanisms by which chronic alcohol ingestion suppresses alveolar macrophage (AM) maturation and immune function and renders individuals susceptible to serious lung infections such as bacterial pneumonia and tuberculosis. Studies during the first phase of this Center demonstrated that alcohol-induced oxidant stress impairs AM differentiation and surface expression of the receptors necessary to drive phagocytosis and the respiratory burst. These derangements could be rescued by oral supplements of GSH precursors. In addition, Center investigators demonstrated that the alcohol-induced oxidant stress increased the expression of transforming growth factor ^ (TOPp^. Since, TGF(3i can increase expression and activity of NADPH oxidase and ROS from NADPH oxidase can up-regulate TGFpi, we hypothesized that chronic alcohol ingestion up-regulates a feed-forward loop of TGFfr and NADPH oxidase that promotes chronic ROS generation and results in impaired AM terminal differentiation. Consequently, impaired terminal differentiation results in AM with decreased plasma membrane expression of the receptors required for triggering phagocytosis and the respiratory burst, thereby rendering the alveolar space vulnerable to infections. In Aims 1-3, a murine model of chronic ethanol ingestion will be employed to examine the relationships between ethanol-induced oxidant stress, NADPH oxidase activation, TGFpi up-regulation, impaired terminal differentiation, and cellular dysfunction in AMs. A unique strength of the Emory Alcohol Center is highlighted through a close collaboration with the Clinical Core in Aim 4, where subjects with or without a history of chronic alcohol abuse will be recruited. After a baseline bronchoalveolar lavage and examination of AMs, subjects will be randomized to treatment with S-adenosylmethionine (SAM) or placebo to determine if SAM can attenuate alcohol-induced derangements in AMs. These studies have the potential to identify novel mechanisms and treatments for pneumonia and lung injury in alcoholic subjects.