Developing and testing novel therapies for the alcoholic lung: our clinical trials pipeline

自成立以来，埃默里酒精和肺生物学中心的主要目标一直是 开发新的和有效的治疗方法，可以减轻甚至逆转的病理生理 酒精对肺的影响前两个供资周期致力于阐明 导致“酒精性肺表型”的基本机制。我们的实验发现 阐明了氧化应激（包括谷胱甘肽严重耗竭）的核心作用，锌 在酒精的作用中，过氧化物酶体增殖物激活受体γ（PPARγ）的表达和功能降低。 最近，我们发现酒精抑制转录因子Nrf 2的作用， 激活抗氧化反应元件（ARE）并以编程方式诱导表达 数百个基因（包括那些参与谷胱甘肽体内平衡的基因）， 对抗炎症压力此外，Nrf 2和PPARγ活性似乎是锌依赖性的， 因此，这些途径可能是相互依赖的，并因此协调地被酒精靶向。 值得注意的是，在慢性HIV感染期间，这些相同的途径是目标，我们已经确定， 酒精和HIV相关蛋白对肺上皮细胞和巨噬细胞具有相加毒性 功能作为我们的中心 研究人员还从事翻译临床试验， 艾滋病毒介导的肺部疾病，我们有独特的能力来研究酒精和 艾滋病毒以及这种组合如何对开发有效的治疗方法构成挑战。这些 这些发现不仅揭示了酒精使肺易受 但也确定了中心研究人员正在测试的候选治疗目标 in experimental实验models模型and clinical临床trials试验.这个新的项目3将协调和指导我们的 “临床试验管道”和牧羊人发现从实验室到干预性试验。 项目3的目标是：1）确定膳食补充锌的功效 和/或SAMe逆转酒精使用障碍受试者的酒精性肺表型， 同时，经常饮酒如何影响饮食锌+ SAMe在逆转肺功能方面的疗效。 艾滋病毒感染者的功能障碍。 2)利用我们的实验和临床翻译 对酒精诱导的抑制PPARγ信号传导的研究进行临床试验，以确定 如果用PPARγ配体吡格列酮治疗可以逆转酒精性肺表型， 酒精使用障碍受试者。3)与项目1和2合作，确定Nrf 2是否 激活剂，单独或与锌结合，可以迅速逆转酒精性肺表型， 动物模型在体内和人肺泡巨噬细胞离体，并将这些研究转化为 在患有以下疾病的受试者中进行的药物如萝卜硫素单独或与锌组合的临床试验 酒精使用障碍我们正在进行的任何这些试验的成功都将对我们产生巨大的影响 对酒精使用障碍患者的影响，包括那些生活在 感染了艾滋病毒

Since its inception, the primary goal of the Emory Alcohol and Lung Biology Center has been to develop novel and effective treatments that can mitigate or even reverse the pathophysiological effects of alcohol on the lung. The first two funding cycles were dedicated to elucidating the fundamental mechanisms that induce the ‘alcoholic lung phenotype’. Our experimental findings have elucidated central roles for oxidative stress (including profound glutathione depletion), zinc deficiency, and decreased expression and function of PPARγ in mediating the effects of alcohol. More recently we identified that alcohol inhibits the actions of Nrf2, the transcription factor that activates the anti-oxidant response element (ARE) and programmatically induces the expression of hundreds of genes (including those involved in glutathione homeostasis) required to defend against inflammatory stresses. Moreover, Nrf2 and PPARγ activity appear to be zinc-dependent and therefore these pathways may be interdependent and therefore coordinately targeted by alcohol. Remarkably, these same pathways are targeted during chronic HIV infection, and we have determined that alcohol and HIV- related proteins have additive toxicities on lung epithelial and macrophage function. As our Center investigators are also engaged in translational clinical trials in HIV-mediated lung disease, we have the unique capacity to study the combined effects of alcohol and HIV and how this combination may pose a challenge to developing effective therapies. These discoveries have not only revealed the mechanisms by which alcohol renders the lung susceptible to injury but have also identified candidate therapies targets that Center investigators are testing in experimental models and clinical trials. This new Project 3 will coordinate and direct our ‘clinical trials pipeline’ and shepherd discoveries from the laboratory to interventional trials. The goals of Project 3 are to: 1) Determine the efficacy of dietary supplementation with zinc and/or SAMe in reversing the alcoholic lung phenotype in subjects with alcohol use disorders and, in parallel, how regular alcohol use affects the efficacy of dietary zinc + SAMe in reversing lung dysfunction in individuals living with HIV. 2) Exploit our experimental and clinical translational studies on alcohol-induced inhibition of PPARγ signaling to conduct a clinical trial to determine if treatment with the PPARγ ligand pioglitazone can reverse the alcoholic lung phenotype in subjects with alcohol use disorders. 3) In collaboration with Projects 1 and 2, determine if Nrf2 activators, alone or in combination with zinc, can rapidly reverse the alcoholic lung phenotype in animal models in vivo and in human alveolar macrophages ex vivo, and translate these studies to a clinical trial of agents such as sulforaphane, alone or in combination with zinc, in subjects with alcohol use disorders. Success in any of these trials in our pipeline will have enormous implications for individuals struggling with alcohol use disorders, including those also living with HIV.