Alcohol and the alveolar epithelial barrier

埃默里酒精和肺生物学中心致力于阐明 酒精使肺容易受到急性水肿性损伤，并开发出新的治疗方法， 降低这些弱势群体的发病率和死亡率。自成立以来， 中心，项目1专注于肺泡上皮，因为这种正常情况下的破坏 屏障紧密是急性肺损伤的主要特征。在第一个筹资周期中 项目1中的研究人员确定，长期饮酒会导致严重的氧化 应激在肺泡腔内，增加细胞旁大分子和液体渗入 呼吸道，如果不加以控制，会导致肺水肿和呼吸衰竭。然而，我们 还发现酒精上调了肺泡上皮跨细胞液体运输 并补偿细胞旁泄漏，从而维持内部正常的气液界面 肺泡。然而，由于系统中没有储备，所以这个新的‘设定点’是不稳定的 酒精上皮对急性炎症应激反应迅速失代偿。在……里面 在第二个(当前)资金周期中，我们延长了这些发现，并确定了肺泡 上皮屏障的完整性依赖于GM-CSF之间的动态平衡，GM-CSF促进 紧密连接的形成和紧密的细胞旁屏障，以及与这些效应相反的转化生长因子β1 并降解细胞旁屏障。最近，该中心的调查人员发现酒精 抑制激活抗氧化剂所需的主转录因子Nrf2 反应元件(ARE)和数百个防御所需基因的程序性诱导 对抗氧化应激。与此同时，我们有挑衅性的新证据表明，Nrf2调控着另一个 主控转录因子PU.1，转导GM-CSF细胞内信号并介导肺 上皮屏障完整性以及巨噬细胞免疫功能。协同抑制作用 依赖NRF2和PU1的细胞功能至少部分是通过酒精诱导的 抑制锌向呼吸道的运输。 值得注意的是，艾滋病毒针对的是这些相同的途径，项目1的调查人员已经确定 酒精和HIV在上皮屏障上的结合比任何一种压力单独作用都更糟糕。 因此，在下一个周期中，项目1将剖析NRF2调节两者的机制 肺泡上皮屏障的组成以及这些酒精如何介导的病理生理学 艾滋病毒的影响加剧了这种影响。同时，肺泡巨噬细胞和肺组织之间的相互作用 调节这一屏障的肺泡上皮细胞作为一个新的研究领域脱颖而出。 与项目2合作，最近发现酒精巨噬细胞 当它与上皮细胞接触时，似乎会释放激活的转化生长因子β1，从而降解 障碍。最后，调查人员将与项目3合作，确定激活剂是否 Nrf2能在体内逆转实验性模型酒精肺表型的基础 与项目3合作设计和启动新的临床试验。

The Emory Alcohol and Lung Biology Center is dedicated to elucidating the mechanisms by which alcohol renders the lung susceptible to acute edematous injury and to developing new therapies that can decrease the morbidity and mortality these vulnerable individuals suffer. Since the inception of the Center, Project 1 has focused on the alveolar epithelium because disruption of this normally tight barrier is a cardinal feature of acute lung injury. In the first funding cycle the investigators in Project 1 determined that chronic alcohol ingestion causes profound oxidative stress within the alveolar space and increases paracellular leak of large molecules and fluid into the airways which, if left unchecked, leads to pulmonary edema and respiratory failure. However, we also identified that alveolar epithelial transcellular fluid transport is up-regulated by alcohol and compensates for the paracellular leak, thereby maintaining a normal air-fluid interface within the alveoli. This new ‘set point’ is nevertheless unstable as there is no reserve in the system and the alcoholic epithelium quickly decompensates in response to an acute inflammatory stress. In the second (current) funding cycle we extended these findings and determined that alveolar epithelial barrier integrity is dependent on the dynamic balance between GM-CSF, which promotes tight junction formation and a tight paracellular barrier, and TGFβ1, which opposes these effects and degrades the paracellular barrier. Most recently, Center investigators identified that alcohol inhibits the master transcription factor Nrf2 that is required to activate the anti-oxidant response element (ARE) and the programmatic induction of hundreds of genes necessary to defend against oxidative stress. In parallel, we have provocative new evidence that Nrf2 regulates another master transcription factor, PU.1 that transduces GM-CSF intracellular signaling and mediates lung epithelial barrier integrity as well as macrophage immune function. The coordinated inhibition of Nrf2- and PU.1-dependent cellular functions is mediated at least in part through alcohol-induced inhibition of zinc transport into the airway. Remarkably, HIV targets these same pathways and Project 1 investigators have identified that the combination of alcohol and HIV on the epithelial barrier is worse than either stress alone. Therefore, in this next cycle Project 1 will dissect the mechanisms by which Nrf2 regulates both components of the alveolar epithelial barrier and how these alcohol-mediated pathophysiological effects are exacerbated by HIV. In parallel, the interactions between the alveolar macrophage and the alveolar epithelium that modulate this barrier come to the fore as a new area of investigation in collaboration with Project 2, driven by the recent discovery that the alcoholic macrophage appears to release activated TGF β1 when it is in contact with the epithelium that degrades the barrier. Finally, in collaboration with Project 3 the investigators will determine if activators of Nrf2 can reverse the alcoholic lung phenotype in experimental models in vivo as the foundation for designing and initiating novel clinical trials in collaboration with Project 3.