Zinc deficiency in the alcoholic lung

酒精肺缺锌

• 批准号: 8299172
• 负责人: David Marshall Guidot
• 金额: $ 26.52万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299172
• 关键词: Acute; Acute Lung Injury; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Alveolar; Alveolar Macrophages; American; Animal Feed; Antioxidants; Bacterial Pneumonia; Binding; Biological Availability; Cell physiology; Cells; Cessation of life; Chronic; Clinical Research; Clinical Trials; Cysteine; Data; Defect; Development; Dietary Zinc; Dose; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Experimental Models; Functional disorder; Genetic Vectors; Glutathione; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor Receptors; Health; Human; Immune; In Vitro; Individual; Infection; Inflammation; Klebsiella pneumonia bacterium; Laboratories; Lung; Lung diseases; Mammalian Cell; Mediating; Metallothionein; Modeling; Molecular; Morbidity - disease rate; Nuclear; Nutrient; Organ; Phagocytosis; Phenotype; Pneumonia; Predisposition; Production; Proteins; Publishing; RNA Interference; Rattus; Recombinant Granulocyte-Macrophage Colony-Stimulating Factors; Recommendation; Relative (related person); Research; Research Proposals; Respiratory Failure; Response Elements; Risk; Risk Factors; Role; Scheme; Signal Transduction; Staging; Sulfhydryl Compounds; Supplementation; Techniques; Testing; Time; Treatment Efficacy; Vulnerable Populations; Zinc; Zinc Fingers; Zinc deficiency; absorption; alcohol use disorder; alveolar epithelium; base; chronic alcohol ingestion; design; feeding; immune function; improved; in vivo; insight; lung injury; macrophage; mortality; novel; novel therapeutics; oxidant stress; preclinical study; prevent; problem drinker; proto-oncogene protein Spi-1; public health relevance; receptor expression; response; restoration; transcription factor; uptake; zinc-binding protein

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. PUBLIC HEALTH RELEVANCE: Alcohol abuse causes many health problems. In particular, even otherwise healthy individuals who consume excessive amounts of alcohol are susceptible to serious lung infections and other causes of respiratory failure, leading to tens of thousands of death in the U.S. alone each year. This project is designed to test the hypothesis that deficiency of the important nutrient zinc is a primary cause of alcohol-related lung injury, and that dietary zinc supplementation could prove to be an effective means of improving lung health in the 15-30 million Americans who suffer from alcohol abuse or dependence.

描述（由申请人提供）：酒精滥用直接影响到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危险因素。实验表明，酒精摄入会引起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，严重损害肺泡巨噬细胞的免疫功能。临床研究证实，即使在健康人群中，慢性酒精滥用也会导致与实验模型相似的严重氧化应激和肺泡巨噬细胞功能障碍。虽然人们早就认识到酒精滥用与锌缺乏有关，而且锌缺乏对免疫细胞功能的损害特别大，但锌的生物利用度在介导酒精性肺表型中的作用尚未得到研究。本应用的初步和已发表的数据表明，锌缺乏导致先前观察到的GM-CSF通过其主转录因子PU.1向肺泡巨噬细胞的信号传导缺陷，但也揭示了新的证据，表明锌缺乏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单一的病理生理学方案中，我们假设酒精抑制锌通过肺泡上皮运输到肺泡间隙，并且由此导致的肺泡巨噬细胞内锌缺乏通过协调干扰其主转录因子来损害GM-CSF信号传导和抗氧化反应因子的激活。此外，我们假设锌补充剂即使不能逆转肺泡巨噬细胞功能障碍，也可以减轻这些易感人群中导致如此多发病率和死亡率的肺泡巨噬细胞功能障碍。本研究计划包括三个综合目标，以检验总体假设；具体而言，慢性酒精摄入会损害锌通过肺泡上皮进入肺泡间隙的运输（Aim 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（Aim 2），并且饮食中补充锌可以长期预防和/或逆转酒精巨噬细胞表型。而GM-CSF和/或硫醇抗氧化剂可以在急性情况下拯救酒精性巨噬细胞（Aim 3）。这个项目不仅对我们理解酒精滥用使肺部易受一系列急性疾病影响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确定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治疗的建议；具体来说，膳食锌补充剂可能潜在地阻止酒精介导的肺部疾病易感性的发展（也可能保护其他目标器官），从而防止或至少限制酒精相关器官损伤，而这些个体正在接受酒精使用障碍的慢性治疗。