Receptor-mediated effects of ethanol in lung tissue injury and repair

描述(申请人提供)：呼吸窘迫综合症是最严重的急性肺损伤形式，已被发现在酗酒者中发生得更频繁。事实上，长期饮酒不仅会增加急性肺损伤的发生率，还会增加死亡率。尽管酒精滥用很重要，但酒精滥用使宿主容易受到急性肺损伤的确切机制仍不清楚。我们已经在肺细胞中发现了一种酒精的细胞表面传感器，并相信它介导了酒精在肺中的许多有害影响。鉴于其被认为的重要性，本项目试图进一步确定这种“酒精受体”的特征，并研究其在慢性酒精暴露环境下急性肺损伤发生中的作用。新的观察结果表明：1)烟碱型乙酰胆碱受体(NAChR)家族的受体成员介导乙醇对肺成纤维细胞的作用；2)乙醇诱导的氧化应激(通过细胞外半胱氨酸/半胱氨酸氧化还原电位的氧化)可能直接激活nAChR。这些观察结果在体内具有重要的意义，因为我们已经表明，患有慢性酒精滥用的受试者在其他方面是健康的，他们表现出氧化应激和肺组织重塑激活的证据。基于以上，我们假设慢性酒精暴露通过作用于肺细胞上存在的nAChRs而使宿主对急性肺损伤易感。此外，我们假设氧化应激可以通过作用于位于受体配体结合位点附近的特定半胱氨酸残基直接激活nAChRs，从而放大这些事件；新的初步数据支持这一假说。最终，由nAChRs触发的下游信号导致一系列事件，使宿主容易受到急性肺损伤。这一假说将在特定的目的下进行检验，目的是：1)表征nAChRs在介导酒精对肺细胞的影响中的作用；2)研究特定形式的氧化剂应激影响乙醇诱导的nAChR激活的机制；3)确定nAChRs在体内介导乙醇诱导的急性肺损伤易感性中的作用。

DESCRIPTION (provided by applicant): Respiratory Distress Syndrome, the most severe form of acute lung injury, has been found to occur more frequently in alcoholics. In fact, chronic alcohol use is not only associated with increased incidence of acute lung injury, but also increased mortality. Despite its importance, the exact mechanisms by which alcohol abuse renders the host susceptible to acute lung injury remain poorly defined. We have identified a cell surface sensor for alcohol in lung cells and believe that it mediates many of the detrimental effects of alcohol in lung. In view of its perceived importance, this project seeks to further characterize this 'alcohol receptor' and investigate its role in the development of acute lung injury in the setting of chronic alcohol exposure. The work proposed was prompted by novel observations showing that: 1) receptors members of the nicotinic acetylcholine receptor (nAChR) family mediate the effects of ethanol in lung fibroblasts and 2) that ethanol-induced oxidant stress (through oxidation of the extracellular cysteine/cystine redox potential) might directly activate nAChRs. These observations have important implications in vivo since we have shown that subjects with chronic alcohol abuse who are otherwise 'healthy' show evidence of oxidant stress as well as activation of lung tissue remodeling. Based on the above, we hypothesize that chronic ethanol exposure renders the host susceptible to acute lung injury by acting on nAChRs present on lung cells. Furthermore, we hypothesize that oxidant stress can amplify these events by activating nAChRs directly through actions on specific cysteine residues strategically located near the ligand binding site of the receptor; new preliminary data support this hypothesis. Ultimately, downstream signals triggered by nAChRs result in a cascade of events that render the host susceptible to acute lung injury. This hypothesis will be tested in specific aims designed to: 1) Characterize the role of nAChRs in mediating the effects of ethanol in lung cells, 2) Examine the mechanisms by which a specific form of oxidant stress influences ethanol-induced nAChR activation, and 3) Determine the role of nAChRs in mediating ethanol-induced susceptibility to acute lung injury in vivo.