Alcohol and the alveolar epithelial barrier

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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.