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

描述（由申请人提供）：呼吸窘迫综合征是急性肺损伤的最严重形式，已发现在酗酒者中更常见。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。尽管其重要性，酒精滥用使主机易受急性肺损伤的确切机制仍然不清楚。我们已经在肺细胞中鉴定了酒精的细胞表面传感器，并认为它介导了酒精在肺中的许多有害影响。鉴于其重要性，本项目旨在进一步描述这种“酒精受体”，并研究其在慢性酒精暴露环境中急性肺损伤发展中的作用。提出的工作是由新的观察结果所提示的：1）烟碱乙酰胆碱受体（nAChR）家族的受体成员介导乙醇在肺成纤维细胞中的作用，2）乙醇诱导的氧化应激（通过细胞外半胱氨酸/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意义，因为我们已经表明，慢性酒精滥用的受试者在其他方面是“健康的”，显示出氧化应激以及肺组织重塑激活的证据。基于上述，我们假设慢性乙醇暴露通过作用于肺细胞上存在的nAChR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直接激活nAChRs来放大这些事件，通过对位于受体配体结合位点附近的特定半胱氨酸残基的作用;新的初步数据支持这一假设。最终，由nAChR触发的下游信号导致级联事件，使宿主易受急性肺损伤的影响。这一假设将在特定的目的进行测试，旨在：1）表征nAChR在介导乙醇对肺细胞的影响中的作用，2）检查特定形式的氧化应激影响乙醇诱导的nAChR激活的机制，3）确定nAChR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.