The mechanisms by which alcohol and HIV render the lung susceptible to injury

描述(由申请人提供)： 项目摘要在过去的25年里，人类免疫缺陷病毒1型(HIV-1)的慢性感染已经成为我们社会面临的最大的健康挑战之一。尽管开发了有效的抗逆转录病毒疗法，但目前这种感染是无法治愈的，感染者必须与一种慢性疾病作斗争，这种疾病会增加他们患肺病、心脏病、肾衰竭和恶性肿瘤的风险。值得注意的是，肺炎和其他肺部并发症是艾滋病毒-1感染者最常见的死亡原因。同时，酗酒是一种常见的慢性病，同样会使个人容易出现包括肺炎和急性肺损伤在内的各种并发症。不幸的是，酗酒往往使艾滋病毒-1感染复杂化，这种组合会对健康造成毁灭性的后果，尤其是对我国退伍军人等弱势群体造成的损害。实验和临床证据揭示了HIV-1和酒精损害肺的潜在共同机制。具体地说，每一种都会导致氧化应激和呼吸道内抗氧化剂谷胱甘肽的耗尽。人体对氧化应激的防御部分取决于细胞激活抗氧化反应元件(ARE)的能力。ARE的激活是由核转录因子Nrf2介导的，Nrf2是一种锌指蛋白，它启动一个遗传程序，刺激包括谷胱甘肽在内的多种抗氧化剂的产生。在实验模型中，慢性酒精摄入抑制了Nrf2的表达和核结合，使肺泡腔内的谷胱甘肽水平降低了80%，并损害了肺泡上皮功能。同时，在实验模型中慢性转基因表达HIV-1也会降低谷胱甘肽水平并损害肺泡上皮功能，而用HIV-1相关蛋白gp120处理肺上皮细胞会抑制Nrf2的表达。这些发现表明，HIV-1和酒精通过抑制Nrf2的表达和/或作用独立地阻断ARE的激活。最近的实验证据表明，长期饮酒与HIV-1转基因表达叠加在一起，比任何一种压力单独造成的肺泡上皮功能障碍都更严重。值得注意的是，这种常见的机制可能涉及锌在牙槽腔内的生物有效性。酒精滥用和HIV-1感染都与人类缺锌有关，在酒精和HIV-1实验模型中，锌水平都显著降低。最有趣的是，饮食补锌改善了酒精喂养和HIV-1转基因动物的肺泡上皮功能，这些有益的效果与增加Nrf2核结合有关。综上所述，这些临床和实验结果表明，酗酒和HIV-1感染都干扰了呼吸道内锌的动态平衡和抗氧化防御的激活，从而使肺容易受到损伤。本项目旨在验证Nrf2表达介导酒精和HIV-1肺表型的假设，以及在此背景下Nrf2的表达受肺泡腔内锌的生物有效性的调节。这一假设将在使用原代大鼠肺泡上皮细胞和体外建立的大鼠肺上皮细胞系的模型系统中进行验证，以及体内有和没有慢性酒精摄入的HIV-1转基因大鼠。这个项目对我们理解酒精滥用和HIV-1感染相互作用增加严重肺损伤风险的基本机制具有重要意义。同时，该项目可能帮助我们改善这些脆弱个体的健康，使用相对简单的膳食补充剂，如单独或与硫醇抗氧化剂(如S-腺苷蛋氨酸)联合使用，这些抗氧化剂也可以改善谷胱甘肽稳态，保护免受氧化损伤。最重要的是，该项目的最终目标是改善退伍军人以及患有艾滋病毒-1感染和/或酗酒的普通民众的健康。

DESCRIPTION (provided by applicant): Project Abstract Chronic infection with human immunodeficiency virus type 1 (HIV-1) has emerged in the past 25 years as one of the greatest health challenges our society has ever faced. Despite the development of effective anti-retroviral regimens, the infection is at present incurable and infected individuals must battle a chronic disease that increases their risk of lung disease, heart disease, kidney failure and malignancies. Notably, pneumonia and other pulmonary complications are the most common causes of death in HIV-1-infected individuals. In parallel, alcohol abuse is a common chronic illness that likewise renders individuals susceptible to diverse complications including pneumonia and acute lung injury. Unfortunately, alcohol abuse often complicates HIV-1 infection, and this combination has devastating health consequences that are particularly damaging to vulnerable populations such as our nation's veterans. Experimental and clinical evidence reveals a potential common mechanism by which HIV-1 and alcohol damage the lung. Specifically, each causes oxidative stress and depletion of the anti-oxidant glutathione within the airways. The body's defenses against oxidative stress depend in part on the ability of cells to activate the anti-oxidant response element (ARE). Activation of the ARE is mediated by the nuclear transcription factor Nrf2, a zinc-finger protein that turns on a genetic program that stimulates the production of multiple anti-oxidants including glutathione. In experimental models, chronic alcohol ingestion inhibits Nrf2 expression and nuclear binding, decreases glutathione levels within the alveolar space by >80%, and impairs alveolar epithelial function. In parallel, chronic HIV-1 transgene expression in experimental models also decreases glutathione levels and impairs alveolar epithelial function, and treatment of lung epithelial cells with the HIV-1-related protein gp120 inhibits Nrf2 expression. These findings suggest that HIV-1 and alcohol independently block activation of the ARE by inhibiting the expression and/or actions of Nrf2. More recent experimental evidence reveals that chronic alcohol ingestion superimposed on HIV-1 transgene expression causes greater alveolar epithelial dysfunction than either stress alone. Remarkably, this common mechanism may involve zinc bioavailability within the alveolar space. Both alcohol abuse and HIV-1 infection are associated with zinc deficiency in humans, and zinc levels are significantly decreased in both the alcohol and HIV-1 experimental models. Most intriguingly, dietary zinc supplementation improves alveolar epithelial function in both alcohol-fed and HIV-1 transgenic animals, and these salutary effects are associated with increased Nrf2 nuclear binding. Taken together, these clinical and experimental findings suggest that alcohol abuse and HIV-1 infection both interfere with zinc homeostasis and activation of anti-oxidant defenses within the airway and thereby render the lung susceptible to injury. This project is designed to test the hypothesis that Nrf2 expression mediates the alcoholic and HIV-1 lung phenotypes, and that Nrf2 expression in this context is modulated by zinc bioavailability within the alveolar space. This hypothesis will be tested in model systems that employ primary rat alveolar epithelial cells and an established rat lung epithelial cell line in vitro, as well as HIV-1 transgenic rats with and without chronic alcohol ingestion in vivo. This project has important implications for our understanding of the basic mechanisms by which alcohol abuse and HIV-1 infection interact to increase the risk of serious lung injury. In parallel, this project may help us improve the health of these vulnerable individuals with relatively simple dietary supplements such as zinc, either alone or in combination with thiol anti-oxidants such as S- adenosylmethionine that can also improve glutathione homeostasis and protect against oxidative injury. Most importantly, the ultimate goal of this project is to improve the health of veterans as well as individuals in the general population who are suffering from HIV-1 infection and/or alcohol abuse.