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

描述（由申请人提供）：呼吸窘迫综合征是最严重的急性肺损伤形式，已被发现在酗酒者中更常见。事实上，长期饮酒不仅与急性肺损伤发生率增加有关，而且与死亡率增加有关。尽管它很重要，但酒精滥用使宿主容易受到急性肺损伤的确切机制仍然不清楚。我们已经确定了肺细胞中酒精的细胞表面传感器，并认为它介导了酒精对肺的许多有害影响。鉴于其重要性，本项目旨在进一步表征这种“酒精受体”，并研究其在慢性酒精暴露下急性肺损伤发展中的作用。提出这项工作的原因是，新的观察结果表明：1)尼古丁乙酰胆碱受体（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”，但却表现出氧化应激和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的nachr使宿主易受急性肺损伤。此外，我们假设氧化应激可以通过直接作用于位于受体配体结合位点附近的特定半胱氨酸残基来激活nAChRs，从而放大这些事件；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一系列事件，使宿主容易受到急性肺损伤。这一假设将在以下特定目标中得到验证：1)表征nAChR在介导乙醇在肺细胞中的作用；2)研究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在介导乙醇诱导的体内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. PUBLIC HEALTH RELEVANCE: Chronic ethanol use has been associated with increased susceptibility to acute lung injury, a condition that affects over 200,000 Americans and that is associated with ~40% mortality. This project will explore how ethanol exposure renders the host susceptible to this condition by examining the cellular mechanisms that mediate the effects of ethanol in lung cells and how this impacts lung injury and repair.