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

描述(由申请人提供)： 酗酒是社会的主要负担，在退伍军人中更是一个问题。长期饮酒可能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，如训练有素的军事人员，即使没有明显的酒精依赖迹象，这种情况也可能突然发生，而且没有任何警告。因此，确定能够限制甚至防止这些毁灭性后果的有效治疗方法，对于我们退伍军人乃至我们全体人民的健康至关重要。这项临床研究项目的主要目标是确定膳食锌或S-腺苷蛋氨酸补充剂是否可以增强其他健康的酗酒者的肺免疫防御，从而降低肺损伤和感染的风险。我们的实验动物模型已经有强有力的证据表明，每天适度饮酒仅六周就会导致氧化还原压力和肺部锌缺乏。经常饮酒会干扰身体从食物中摄取锌并将其输送到肺部的能力，而锌对正常的免疫功能和肺部的整体健康是必不可少的。对动物模型的研究表明，肺部的氧化应激和缺锌会导致常驻免疫细胞肺泡巨噬细胞功能障碍，并使动物容易患上肺炎。重要的是，在这个相同的动物模型中，我们发现在饮食中添加锌或谷胱甘肽可以防止这些问题，并保护肺部健康，即使在日常饮酒期间也是如此。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补充剂对病理性饮酒的人类是否有效。与动物模型数据类似，我们来自其他健康的酒精中毒志愿者的初步结果表明，肺部既存在锌缺乏，也存在氧化应激。该项目将扩展这些发现，并将亚特兰大退伍军人医院开始酒精治疗的退伍军人纳入物质滥用治疗计划(SATP)。参与者将接受评估，方法是从他们的肺部获取液体样本，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情况(通过测定吞噬能力)。在完成初步评估后，参与者将随机接受标准治疗(安慰剂)、锌补充剂或饮食SAM，为期14天。所有受试者在接受治疗时都将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。假设膳食锌和SAM补充剂都能提高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补充剂是否在急性临床环境下也能有效，并改善患肺炎或急性肺损伤的酗酒者的预后。锌补充剂和SAM补充剂都是安全、简单和廉价的，使这些潜在的治疗方法很容易在退伍军人群体和整个社会实施。鉴于不健康饮酒造成的巨大负担，我们迫切需要找到方法，在继续努力进行公共教育和成瘾治疗的同时，限制酒精滥用对这一弱势群体的身体后果。

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.