Alcohol abuse, oxidative stress, and zinc deficiency in lung disease

描述（由申请人提供）： 酗酒是社会的一个主要负担，在退伍军人中更是一个问题。 长期摄入酒精会造成严重的健康后果，包括肺炎和急性肺损伤，即使在身体健康的人，如受过训练的军事人员，即使没有明显的酒精依赖迹象，也会突然发生，没有任何警告。因此，对于我们的退伍军人和我们整个人口的健康至关重要，以确定可以限制甚至预防这些破坏性后果的有效治疗方法。该临床研究项目的主要目标是确定膳食锌或S-腺苷甲硫氨酸（SAM）补充剂是否可以增强健康酗酒者的肺部免疫防御，从而降低肺损伤和感染的风险。从我们的实验动物模型中已经有强有力的证据表明，每天适度摄入酒精，持续六周，会导致肺中的氧化还原应激和锌缺乏。经常饮酒会干扰身体从食物中吸收锌并将其输送到肺部的能力，而肺部对正常的免疫功能和肺部的整体健康至关重要。对动物模型的研究表明，肺中的氧化应激和锌缺乏导致肺泡巨噬细胞功能障碍，肺泡巨噬细胞是常驻免疫细胞，并使动物易于发生肺炎。重要的是，在同一动物模型中，我们发现在饮食中添加锌或谷胱甘肽可以预防这些问题，即使在日常饮酒期间也可以保持肺部健康。 该CDA-2项目将把动物模型中的基本发现转化为临床环境，并确定锌或SAM补充剂是否对病理性饮酒的人有效。与动物模型数据平行，我们对其他健康酒精志愿者的初步结果表明，肺中存在锌缺乏和氧化应激。该项目将扩展这些发现，并招募在亚特兰大退伍军人医院开始酒精治疗的退伍军人参加药物滥用治疗计划（SATP）。参与者将接受一项程序进行评估，以从他们的肺部获得液体样本，测量锌水平，氧化还原电位，并评估他们的肺泡巨噬细胞对细菌的反应（通过确定吞噬能力）。完成初步评估后，参与者将随机接受标准治疗（安慰剂），锌补充剂或膳食SAM，持续14天。所有受试者将在接受治疗时接受为期两周的评估。在这两周结束时，将重复测量肺锌、氧化还原电位和巨噬细胞功能，并在两组之间进行比较。假设是膳食锌和SAM补充剂都将改善肺泡巨噬细胞的免疫功能（如细菌吞噬能力所反映的）。 如果该项目成功，它将导致更大规模的临床试验，以确定膳食锌或SAM补充剂是否即使在急性临床环境中也有效，并改善患有肺炎或急性肺损伤的酗酒者的结果。锌和SAM补充剂都是安全，简单和廉价的，使这些潜在的治疗方法可以很容易地在退伍军人群体以及整个社会中实施。鉴于不健康的酒精使用造成的巨大负担，我们迫切需要找到方法，限制酒精滥用对这一弱势群体的身体影响，同时我们继续努力进行公共教育和成瘾治疗。

DESCRIPTION (provided by applicant): Alcohol abuse is a major burden on society and even more of a problem in the veteran population. Chronic alcohol ingestion can have serious health consequences including pneumonia and acute lung injury, which can occur suddenly and without warning even in physically fit individuals, such as trained military personnel, even without apparent signs of alcohol dependence. Therefore, it is vital for the health of our veterans and indeed our entire population to identify effective treatments that can limit or even prevent these devastating consequences. The primary goal of this clinical research project is to determine if either dietary zinc or S-adenosylmethionine (SAM) supplements can augment lung immune defenses in otherwise healthy alcoholics and thereby decrease the risk of lung injury and infection. There is already strong evidence from our experimental animal models that moderate daily alcohol ingestion for as little as six weeks causes both redox stress and zinc deficiency in the lung. Regular alcohol consumption interferes with the body's ability to take in zinc from food and deliver it to the lung where it is essential for normal immune function and overall health of the lung. Research in the animal model suggests that oxidative stress and zinc deficiency in the lung result in dysfunction of the alveolar macrophage, which is the resident immune cell, and predisposes animals to the development of pneumonia. Importantly, in this same animal model, we found that adding either zinc or glutathione to the diet prevents these problems and preserves lung health even during daily alcohol ingestion. This CDA-2 project will translate basic findings in the animal model to the clinical setting and determine whether or not zinc or SAM supplements are effective in humans who pathologically consume alcohol. Parallel to the animal model data, our preliminary results from otherwise healthy alcoholic volunteers shows there exists both zinc deficiency and oxidative stress in the lung. This project will extend these findings and enroll veterans who are beginning alcohol treatment at the Atlanta Veterans Hospital in the Substance Abuse Treatment Program (SATP). Participants will be evaluated by undergoing a procedure to obtain samples of fluid from their lungs, measure zinc levels, redox potential, and assess how well their alveolar macrophages respond to bacteria (by determining phagocytic capacity). After completion of the initial evaluation, the participants will be randomized to receive standard treatment (placebo), zinc supplements, or dietary SAM for 14 days. All subjects will be evaluated for two weeks as they undergo treatment. At the end of this two week period, measurements of lung zinc, redox potential and macrophage function will be repeated and compared between the two groups. The hypothesis is that both dietary zinc and SAM supplements will improve alveolar macrophage immune function (as reflected by bacterial phagocytic capacity). If this project is successful, it will lead to larger scale clinical trials o determine if either dietary zinc or SAM supplements can be effective even in the acute clinical setting and improve outcomes in alcoholics who develop pneumonia or acute lung injury. Both zinc and SAM supplements are safe, simple, and inexpensive to provide, allowing these potential treatments to be easily implemented in the veteran population as well as society in general. Given the significant burden of unhealthy alcohol use, we desperately need to find ways to limit the physical consequences of alcohol abuse in this vulnerable population while we continue the efforts at public education and addiction treatment.