Zinc deficiency in the alcoholic lung

酒精肺缺锌

• 批准号: 8497548
• 负责人: David Marshall Guidot
• 金额: $ 24.67万
• 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/8497548
• 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.

描述（由申请人提供）：酗酒直接影响1,3000万美国人，是多种肺炎在内的几种毁灭性肺部疾病的主要危险因素。在实验上，酒精摄入会导致肺泡空间内的氧化应激，并严重损害了肺泡巨噬细胞免疫功能，通过抑制GM-CSF信号传导和这些细胞的启动。临床研究已经证实，即使在健康的人类中，慢性酒精滥用也会引起严重的氧化应激和肺泡巨噬细胞功能障碍，使实验模型平行。尽管长期以来一直认识到酗酒与锌缺乏有关，并且锌缺乏症对免疫细胞功能特别损害，但尚未研究锌生物利用度在介导酒精肺表型中的作用。该应用程序中的初步和已发表的数据暗示，通过其主转录因子PU.1，GM-CSF信号中先前观察到的缺陷向肺泡巨噬细胞中观察到的锌缺乏症，但也揭示了锌缺陷抑制抗氧化剂响应元件的激活，从而抑制了抗氧化剂响应元件的激活，从而抑制其主转录因子NRF2。为了将这些发现统一为单一的病理生理方案，我们假设酒精会抑制牙槽上皮的锌传输到肺泡空间中，并且肺泡巨噬细胞内随之而来的锌缺乏症会影响GM-CSF信号传导和通过与他们的大师转录相互作用的抗氧化反应元素的激活，从而促进GM-CSF信号传导和激活。此外，我们假设补充锌可以减轻肺泡巨噬细胞功能障碍，从而导致这些脆弱个体的发病率和死亡率如此之多。这项研究建议包括三个综合目的来检验总体假设。 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和/或硫醇抗氧化剂可以在急性环境中拯救酒精巨噬细胞（AIM 3）。该项目不仅对我们对酒精滥用使肺部容易受到一系列急性疾病的基本机制的理解具有重要意义，而且还鉴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型治疗策略的能力。此外，该项目的结果可能会改变我们治疗慢性酒精滥用的建议。具体而言，补充饮食锌可能有可能防止饮酒介导的对肺部疾病的易感性（也许也可以保护其他靶器官），从而预防或至少限制与酒精相关的器官损害，而这些人对其酒精使用障碍进行了长期治疗。