Zinc deficiency in the alcoholic lung

描述（由申请人提供）：酗酒直接影响 15-3000 万美国人，是包括肺炎在内的多种毁灭性肺部疾病的主要危险因素。实验上，摄入酒精会导致肺泡腔内的氧化应激，并通过抑制 GM-CSF 信号传导和这些细胞的启动而严重损害肺泡巨噬细胞的免疫功能。临床研究已经证实，即使在其他方面健康的人中，长期酗酒也会导致严重的氧化应激和肺泡巨噬细胞功能障碍，这与实验模型相似。尽管人们早已认识到酗酒与锌缺乏有关，并且锌缺乏尤其会损害免疫细胞功能，但锌生物利用度在介导酒精性肺表型中的作用尚未得到研究。本申请中的初步和已发表的数据表明，先前观察到的 GM-CSF 通过其主转录因子 PU.1 向肺泡巨噬细胞发出信号的缺陷中存在缺锌，但也揭示了新的证据，表明缺锌通过抑制其主转录因子 Nrf2 的表达来抑制抗氧化反应元件的激活。为了将这些发现统一到一个病理生理学方案中，我们假设酒精抑制锌通过肺泡上皮转运到肺泡腔，并且随之而来的肺泡巨噬细胞内的锌缺乏通过协调干扰其主转录因子而损害GM-CSF信号传导和抗氧化反应元件的激活。此外，我们假设补充锌可以减轻（如果不能逆转）肺泡巨噬细胞功能障碍，而肺泡巨噬细胞功能障碍会导致这些脆弱个体的发病率和死亡率如此之高。该研究计划包括三个综合目标来检验总体假设；具体来说，慢性酒精摄入会损害锌穿过肺泡上皮进入肺泡腔的转运（目标 1），从而导致肺泡巨噬细胞内缺锌，从而干扰通过抗氧化反应元件和 GM-CSF 的关键信号传导（目标 2），并且膳食补锌可以长期预防和/或逆转酒精性巨噬细胞表型，而 GM-CSF 和/或硫醇抗氧化剂可以在急性环境下拯救酒精性巨噬细胞（目标 3）。该项目不仅对我们了解酗酒导致肺部易患一系列急性疾病的基本机制具有重要意义，而且对我们在针对这一高度脆弱人群的临床试验中识别和测试新治疗策略的能力具有重要意义。此外，该项目的结果可能会改变我们对治疗慢性酒精滥用的建议；具体而言，膳食补锌可能会预防酒精介导的肺部疾病易感性的发展（或许还可以保护其他靶器官），从而在这些人接受酒精使用障碍的长期治疗时预防或至少限制与酒精相关的器官损伤。

DESCRIPTION (provided by applicant): Alcohol abuse directly affects 15-30 million Americans and is a major risk factor for several devastating lung diseases including pneumonia. Experimentally, alcohol ingestion causes oxidant stress within the alveolar space and severely compromises alveolar macrophage immune function by dampening GM-CSF signaling and priming of these cells. Clinical studies have verified that chronic alcohol abuse, even in otherwise healthy humans, causes severe oxidant stress and alveolar macrophage dysfunction that parallel the experimental models. Although it has long been recognized that alcohol abuse is associated with zinc deficiency, and that zinc deficiency is particularly damaging to immune cell functions, the role of zinc bioavailability in mediating the alcoholic lung phenotype has not been investigated. Preliminary and published data in this application implicate zinc deficiency in the previously observed defects in GM-CSF signaling to the alveolar macrophage through its master transcription factor, PU.1, but also reveal new evidence that zinc deficiency suppresses activation of the antioxidant response element by inhibiting expression of its master transcription factor, Nrf2. To unify these findings into a single pathophysiological scheme, we hypothesize that alcohol inhibits zinc transport by the alveolar epithelium into the alveolar space, and that the consequent zinc deficiency within the alveolar macrophage impairs both GM-CSF signaling and activation of the antioxidant response element by coordinately interfering with their master transcription factors. Further, we hypothesize that zinc supplementation can mitigate if not reverse the alveolar macrophage dysfunction that causes so much morbidity and mortality in these vulnerable individuals. This research proposal includes three integrated aims that test the overarching hypothesis; specifically, that chronic alcohol ingestion impairs zinc transport across the alveolar epithelium into the alveolar space (Aim 1), which leads to zinc deficiency within the alveolar macrophage that interferes with critical signaling through the antioxidant response element and GM-CSF (Aim 2), and that dietary zinc supplementation can prevent and/or reverse the alcoholic macrophage phenotype in the long-term, whereas GM-CSF and/or thiol antioxidants can rescue the alcoholic macrophage in the acute setting (Aim 3). This project has important implications not only for our understanding of the fundamental mechanisms by which alcohol abuse renders the lung susceptible to a range of acute illnesses, but also for our ability to identify and test novel therapeutic strategies in clinical trials targeted to this highly vulnerable population. Further, the results of this project could change our recommendations for treatment of chronic alcohol abuse; specifically, dietary zinc supplementation could potentially prevent the development of alcohol- mediated susceptibility to lung diseases (and perhaps protect other target organs as well), and thereby prevent or at least limit alcohol-related organ damage while these individuals undergo chronic treatment for their alcohol use disorders.