Zinc deficiency in the alcoholic lung

描述(申请人提供)：酗酒直接影响1500万至3000万美国人，是包括肺炎在内的几种破坏性肺部疾病的主要风险因素。实验上，酒精摄入会导致肺泡腔内的氧化应激，并通过抑制GM-CSF信号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，慢性酒精滥用，即使在其他健康的人身上，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。虽然人们早就认识到酒精滥用与缺锌有关，缺锌对免疫细胞功能的损害尤其严重，但锌的生物利用度在调节酒精性肺表型中的作用尚未被研究。在这一应用中的初步和发表的数据表明，缺锌与先前观察到的GM-CSF通过其主要转录因子PU.1向肺泡巨噬细胞发送信号的缺陷有关，但也揭示了新的证据，即缺锌通过抑制其主要转录因子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单一的病理生理学方案中，我们假设酒精抑制了肺泡上皮细胞向肺泡腔的锌运输，随后肺泡巨噬细胞内的锌缺乏通过协调干扰它们的主要转录因子来损害GM-CSF信号和抗氧化反应元件的激活。此外，我们假设补锌可以缓解或逆转肺泡巨噬细胞功能障碍，而肺泡巨噬细胞功能障碍是导致这些脆弱个体如此多的发病率和死亡率的原因。这项研究建议包括三个综合目标来检验这一最重要的假说；具体地说，长期饮酒会损害锌从肺泡上皮到肺泡腔的转运(目标1)，从而导致肺泡巨噬细胞内锌缺乏，从而干扰通过抗氧化反应元件和GM-CSF的关键信号(目标2)，从长远来看，膳食补锌可以防止和/或逆转酒精巨噬细胞的表型，而GM-CSF和/或硫醇抗氧化剂可以在急性情况下拯救酒精巨噬细胞(目标3)。这个项目不仅对我们理解酒精滥用导致肺部易患一系列急性疾病的基本机制具有重要意义，而且对于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的治疗策略的能力也具有重要意义。此外，该项目的结果可能会改变我们对慢性酒精滥用的治疗建议；具体地说，膳食补锌可能会防止酒精引起的肺部疾病易感性的发展(也许还会保护其他靶器官)，从而在这些人接受酒精使用障碍的慢性治疗时防止或至少限制与酒精相关的器官损害。

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.