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

酒精和艾滋病毒使肺部容易受伤的机制

• 批准号: 8597368
• 负责人: David Marshall Guidot
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597368
• 关键词: Acute; Acute Lung Injury; Alcohol abuse; Alcohol consumption; Alcohols; Alveolar; Anti-Retroviral Agents; Antioxidants; Aspiration Pneumonia; Attenuated; Binding; Biological Availability; Biological Models; Cause of Death; Cell Line; Cells; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Research; Development; Dietary Supplementation; Dietary Zinc; Endotoxemia; Epithelial; Epithelial Cells; Experimental Animal Model; Experimental Models; Functional disorder; General Population; Genetic Programming; Genome; Glutathione; Goals; HIV; HIV Envelope Protein gp120; HIV-1; Health; Heart Diseases; Heavy Drinking; Homeostasis; Human; In Vitro; Individual; Infection; Inflammatory; Injury; Kidney Failure; Laboratories; Life; Lung; Lung diseases; Malignant Neoplasms; Mammalian Cell; Mediating; Morbidity - disease rate; Nuclear; Oxidative Stress; Permeability; Personal Satisfaction; Phenotype; Play; Pneumonia; Population; Preparation; Production; Program Reviews; Proteins; Publishing; RNA Interference; Rattus; Regimen; Research; Research Personnel; Research Project Grants; Respiratory Failure; Response Elements; Risk; Role; S-Adenosylmethionine; Sepsis; Societies; Stress; Sulfhydryl Compounds; Supplementation; Testing; Tight Junctions; Transgenic Animals; Transgenic Organisms; Translating; Trauma; Veterans; Vulnerable Populations; Zinc; Zinc Fingers; Zinc deficiency; abstracting; alcohol effect; alcohol exposure; alcohol use disorder; alveolar epithelium; chronic alcohol ingestion; design; dietary supplements; disability; effective therapy; feeding; improved; in vivo; lung injury; mortality; novel; novel therapeutics; outcome forecast; preclinical study; prevent; problem drinker; programs; public health relevance; response; transcription factor; transgene expression; uptake

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.

描述（由申请人提供）： 在过去的25年中，Project摘要慢性感染具有人类免疫缺陷病毒1型（HIV-1），这是我们社会有史以来最大的健康挑战之一。尽管发展有效的抗逆转录病毒方案，但目前感染仍无法治愈，受感染的个体必须与慢性疾病作斗争，以增加其肺部疾病，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感染者中最常见的死亡原因。同时，酗酒是一种常见的慢性疾病，它同样使人容易受到包括肺炎和急性肺损伤在内的各种并发症。不幸的是，酗酒通常会使HIV-1感染复杂化，这种结合具有破坏性的健康后果，这对我们国家的退伍军人等脆弱人群尤其损害。实验和临床证据揭示了HIV-1和酒精损害肺的潜在常见机制。具体而言，每种都会导致抗氧化剂谷胱甘肽在气道中的氧化应激和耗竭。人体针对氧化应激的防御能力部分取决于细胞激活抗氧化反应元件（AS）的能力。核转录因子NRF2介导的激活是一种锌指蛋白，该锌指蛋白打开了遗传程序，该程序刺激了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NRF2表达和核结合，使肺泡空间内的谷胱甘肽水平降低> 80％，并损害肺泡上皮功能。同时，实验模型中的慢性HIV-1转基因表达还降低了谷胱甘肽水平并损害肺泡上皮功能，并用HIV-1相关蛋白GP120抑制NRF2表达，肺上皮细胞的处理。这些发现表明，HIV-1和酒精独立地阻止了该nrf2的表达和/或作用，从而独立阻断了该活力的激活。最新的实验证据表明，叠加在HIV-1转基因表达上的慢性酒精摄入会导致肺泡上皮功能障碍比单独的任何压力更大。值得注意的是，这种常见机制可能涉及肺泡空间内的锌生物利用度。酒精滥用和HIV-1感染都与人类的锌缺乏有关，在酒精和HIV-1实验模型中，锌水平都显着降低。最有趣的是，饮食锌补充剂可改善酒精喂养和HIV-1转基因动物的肺泡上皮功能，这些有益的作用与NRF2核结合的增加有关。综上所述，这些临床和实验性发现表明，酒精滥用和HIV-1感染都干扰了锌稳态以及气道内抗氧化剂防御的激活，从而使肺部易于受伤。该项目旨在检验以下假设：NRF2表达介导了酒精和HIV-1肺表型，并且在这种情况下，NRF2表达在肺泡空间内的锌生物利用度调节。该假设将在使用原发性大鼠肺泡上皮细胞和已建立的大鼠肺上皮细胞系以及体内慢性酒精摄入的HIV-1转基因大鼠中进行测试。该项目对我们对酗酒和HIV-1感染相互作用以增加严重肺损伤的风险的基本机制具有重要意义。同时，该项目可以帮助我们改善这些脆弱的人的健康，无论是单独或与硫醇抗氧化剂（例如s-腺苷硫代氨酸）结合使用，例如锌，例如锌，也可以改善谷胱甘肽稳态并预防氧化损伤。最重要的是，该项目的最终目标是改善患有HIV-1感染和/或酗酒的普通民众的退伍军人和个人的健康。 公共卫生相关性： 对人类免疫缺陷病毒1型（HIV-1）和酗酒的叙事叙事慢性感染均对退伍军人人口的福祉造成了巨大的伤害，并且结合结合对这些脆弱的人造成了破坏性的健康后果。尽管有效的抗逆转录病毒疗法的发展改善了HIV-1感染者的预后，但它仍然是一种无法治愈的慢性疾病，会导致极大的发病率和死亡率。不幸的是，HIV-1感染通常会因酗酒而复杂化，这是我们帮助退伍军人过着健康生活的主要挑战。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以及没有特定疗法的损害知之甚少。该研究项目旨在确定酒精和HIV-1如何相互作用以使肺部容易受到伤害，并开发有效的治疗方法，以改善这些脆弱者的健康状况。