RC#1: Alcohol and the Alveolar Epithelial Barrier

埃默里酒精和肺生物学中心竞争性更新中的基本和统一假设是，慢性酒精滥用会导致氧化应激并破坏正常的调节途径， 产生一种“酒精肺表型”，对呼吸道感染、急性肺损伤和其他严重肺部疾病高度敏感。肺泡上皮屏障的破坏是严重肺结核的主要特征。 感染、创伤、胰腺炎和胃吸入等损伤导致的肺损伤;这些损伤中的任何一种都可引起急性呼吸窘迫综合征（ARDS），这是一种毁灭性的急性肺损伤， 死亡率为40- 60%。重要的是，埃默里酒精和肺生物学中心的研究人员已经确定，酒精滥用独立增加ARDS的风险约4倍。肺泡上皮屏障由至少三种重要成分组成：肺泡I型（AT 1）细胞、肺泡2型（AT 2）细胞、肺泡上皮细胞和肺泡上皮细胞。 细胞，以及将这些细胞结合在一起的紧密连接。所有这三种成分都受到调节，并有助于正常的屏障功能。在这次竞争性续约中，项目调查人员将利用 新的发现，在以前的周期，并将确定精确的分子机制，肺泡上皮屏障受损的酒精肺。上一周期和新周期的研究 在该更新申请中提出的初步发现揭示了由粒细胞/巨噬细胞集落刺激因子（GM-CSF）和转化生长因子B1（TGFB 1）介导的两种关键信号转导途径对肺泡上皮具有拮抗作用：GM-CSF促进屏障完整性，而TGFB 1诱导屏障破坏。在项目1中，研究人员假设酒精诱导的氧化应激，以及随之而来的GM-CSF和TGFB 1之间信号平衡的转变，使肺泡上皮紧密连接不稳定，并使酒精性肺更容易受到急性水肿性损伤。该项目的研究人员将使用他们建立的大鼠慢性酒精摄入动物模型来确定GM-CSF和TGFB 1信号传导的这种不平衡长期改变正常紧密的肺泡上皮屏障的离散机制，以及这种不平衡如何加剧并导致脓毒症和其他炎症性损伤的急性水肿损伤。此外，他们将通过与临床核心的直接合作将这些研究转化为临床环境。拟议的研究对我们理解酒精滥用使其他健康个体处于ARDS高风险的机制以及我们设计和测试新的治疗干预措施的能力具有重要意义。

The fundamental and unifying hypothesis in the Emory Alcohol and Lung Biology Center competitive renewal is that chronic alcohol abuse causes oxidant stress and disrupts normal regulatory pathways, thereby producing an "alcoholic lung phenotype" that is highly susceptible to respiratory infections, acute lung injury, and other serious lung diseases. Disruption of the alveolar epithelial barrier is a cardinal feature of serious lung injuries from insults such as infection, trauma, pancreatitis, and gastric aspiration; any of these insults can cause the acute respiratory distress syndrome (ARDS), a devastating form of acute lung injury with a mortality of 40-60%. Importantly, investigators in the Emory Alcohol and Lung Biology Center have determined that alcohol abuse independently increases the risk of ARDS ~4-fold. The alveolar epithelial barrier consists of at least three important components: alveolar type I (AT1) cells, alveolar type 2 (AT2) cells, and the tight junctions that bind these cells together. All three components are regulated and contribute to normal barrier function. In this competitive renewal the project investigators will capitalize on the novel discoveries made in the previous cycle and will define the precise molecular mechanisms by which the alveolar epithelial barrier is impaired in the alcoholic lung. The studies in the previous cycle and new preliminary findings presented in this renewal application reveal that two key signal transduction pathways, mediated by granulocyte/macrophage colony-stimulating factor (GM-CSF) and transforming growth factor B1 (TGFB1), have antagonistic effects on the alveolar epithelium: GM-CSF promotes barrier integrity whereas TGFB1 induces barrier disruption. In Project 1, the investigators hypothesize that alcohol-induced oxidant stress, and the consequent shift in the signaling balance between GM-CSF and TGFB1, destabilizes alveolar epithelial tight junctions and renders the alcoholic lung more vulnerable to acute edematous injury. The investigators in this project will use their established animal model of chronic alcohol ingestion in rats to determine the discrete mechanisms by which this imbalance in GM-CSF and TGFB1, signaling alters the normally tight alveolar epithelial barrier chronically, as well as how this imbalance is exacerbated and contributes to acute edematous injury in response to sepsis and other inflammatory insults. Further, they will translate these studies to the clinical setting through direct collaborations with the Clinical Core. The proposed studies have enromous implications for our understanding of the mechanisms by which alcohol abuse renders otherwise healthy individuals at high risk for ARDS, as well as our ability to design and test novel therapeutic interventions.