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

描述（由申请人提供）： 人类免疫缺陷病毒1型（HIV-1）的慢性感染在过去25年中已经成为我们社会面临的最大健康挑战之一。尽管开发了有效的抗逆转录病毒疗法，但这种感染目前无法治愈，受感染者必须与一种慢性疾病作斗争，这种疾病增加了他们患肺病、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HIV-1感染者最常见的死亡原因。同时，酒精滥用是一种常见的慢性疾病，同样使个人容易患上各种并发症，包括肺炎和急性肺损伤。不幸的是，酗酒往往使HIV-1感染复杂化，这种结合具有破坏性的健康后果，特别是对我国退伍军人等弱势群体的损害。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，每种都引起呼吸道内的氧化应激和抗氧化剂谷胱甘肽的消耗。身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Nrf 2介导的，Nrf 2是一种锌指蛋白，它开启一种遗传程序，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Nrf 2表达和核结合，使肺泡腔内谷胱甘肽水平降低> 80%，并损害肺泡上皮功能。同时，实验模型中的慢性HIV-1转基因表达也降低谷胱甘肽水平并损害肺泡上皮功能，用HIV-1相关蛋白gp 120治疗肺上皮细胞可抑制Nrf 2表达。这些发现表明，HIV-1和酒精通过抑制Nrf 2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，慢性酒精摄入叠加HIV-1转基因表达导致更大的肺泡上皮细胞功能障碍比单独的压力。值得注意的是，这种常见的机制可能涉及肺泡腔内锌的生物利用度。酒精滥用和HIV-1感染都与人类锌缺乏有关，在酒精和HIV-1实验模型中锌水平显着下降。最有趣的是，膳食锌补充剂改善了酒精喂养和HIV-1转基因动物的肺泡上皮功能，这些有益的作用与增加Nrf 2核结合有关。总之，这些临床和实验结果表明，酒精滥用和HIV-1感染都干扰锌稳态和气道内抗氧化防御的激活，从而使肺易受损伤。该项目旨在检验Nrf 2表达介导酒精和HIV-1肺表型的假设，以及在这种情况下Nrf 2表达受肺泡腔内锌生物利用度的调节。这一假设将在模型系统中进行测试，该模型系统采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，以及体内有和无慢性酒精摄入的HIV-1转基因大鼠。该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。与此同时，该项目可以帮助我们改善这些脆弱个体的健康，这些脆弱个体具有相对简单的膳食补充剂，例如锌，单独或与巯基抗氧化剂如S-腺苷甲硫氨酸组合，也可以改善谷胱甘肽体内平衡并防止氧化损伤。最重要的是，该项目的最终目标是改善退伍军人以及普通人群中感染艾滋病毒-1和/或酗酒者的健康。 公共卫生相关性： 1型人类免疫缺陷病毒（HIV-1）的慢性感染和酗酒都对退伍军人的健康造成了巨大的损害，两者结合起来对这些脆弱的个体产生了毁灭性的健康后果。虽然有效的抗逆转录病毒疗法的发展改善了艾滋病毒-1感染者的预后，但它仍然是一种无法治愈的慢性疾病，造成很高的发病率和死亡率。不幸的是，HIV-1感染往往因酗酒而复杂化，这是我们帮助退伍军人过上健康生活的目标面临的一个重大挑战。肺是这些退伍军人的常见目标，急性和慢性呼吸衰竭是残疾和早期死亡的主要原因。目前，我们对HIV-1和酒精如何损害肺部知之甚少，也没有具体的治疗方法。该研究项目旨在确定酒精和HIV-1如何相互作用，使肺部易受损伤，并开发有效的治疗方法，以改善这些脆弱个体的健康。

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. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic infection with the human immunodeficiency virus type 1 (HIV-1) and alcohol abuse each take an enormous toll on the well-being of the veteran population, and in combination produce devastating health consequences for these vulnerable individuals. Although the development of effective anti-retroviral therapies has improved the prognosis for HIV-1-infected individuals, it remains an incurable chronic illness that causes great morbidity and mortality. Unfortunately, HIV-1 infection is often complicated by alcohol abuse and this is a major challenge in our goal of helping veterans live healthy lives. The lung is a common target in these veterans, and acute and chronic forms of respiratory failure are a major cause of disability and early death. At present, we know very little about how HIV-1 and alcohol damage the lung and there are no specific therapies. This research project is designed to determine how alcohol and HIV-1 interact to make the lung susceptible to injury, and to develop effective treatments that can improve the health of these vulnerable individuals.