Role of AC7 and alcohol in innate immune responses during bacterial infection

项目概要/摘要 酒精消耗损害免疫防御系统的各种组成部分的功能， 在人类和动物模型中调节先天性和适应性免疫。然而，机制 乙醇对免疫系统的影响的原因还不完全清楚。众所周知， AMP（cAMP）调节免疫反应;然而，是否有特定的腺苷酸环化酶（AC）亚型， 主要负责介导乙醇对免疫反应的影响， 测定我们的长期目标是阐明a）AC的哪些特定亚型调节乙醇的 对免疫应答的影响，和B）这种调节的潜在机制。 使用骨髓谱系特异性7型AC亚型（AC 7）敲除小鼠，我们的初步数据表明， 急性乙醇摄入对肺中细胞因子表达的抑制作用需要AC 7表达， 骨髓细胞因此，我们假设AC 7在调节急性酒精作用中起关键作用。 对免疫系统的影响我们假设急性摄入酒精会导致一种或多种 更多的GS偶联受体激动剂局部存在于肺中或全身存在于循环中。反过来， 刺激骨髓细胞如肺泡巨噬细胞中的AC 7活性，导致免疫抑制 应答在这个提议中，我们将利用髓系特异性AC 7敲除小鼠。我们将雇用敏锐的 酒精摄入结合活菌腹腔注射，以阐明乙醇 通过AC 7活性抑制先天免疫应答。这是一个成熟的急性肺损伤小鼠模型， 在人类中由脓毒症引起的损伤。该提案的具体目标是目标1：确定先天免疫 骨髓谱系特异性AC 7敲除小鼠的肺中响应于细菌感染的应答 目的2：定量Gs-coupled受体激动剂， 用酒精处理的动物的支气管肺泡灌洗液和血浆以及肺中的cAMP水平 和活细菌。我们假设腺苷、肾上腺素和前列腺素E2是 急性乙醇摄入增加葡萄糖偶联受体激动剂。拟议的研究简明扼要，重点突出 急性酒精对细菌感染引起的肺部炎症的影响。拟议研究的结果 将通过AC 7活性产生关于酒精对免疫系统影响的机制信息。 从这项研究中获得的数据将成为未来研究的基础， 详细研究了酒精对免疫系统的影响，并可能导致药物干预，以对抗 酒精摄入的负面影响。

Project Summary/Abstract Alcohol consumption compromises the function of various components of the immune defense system by modulating innate and adaptive immunity in both humans and animal models. However, the mechanisms responsible for ethanol’s effects on the immune system are not fully understood. It is well established that cyclic AMP (cAMP) regulates immune responses; however, whether a specific adenylyl cyclase (AC) isoform is primarily responsible for mediating on ethanol’s effects on immune responses has not yet been clearly determined. Our long-term goal is to elucidate a) which specific isoform(s) of AC modulate(s) ethanol’s effects on immune responses, and b) the mechanisms underlying this modulation. Using myeloid lineage specific type 7 AC isoform (AC7) knockout mice, our preliminary data indicate that the suppressive effect of acute ethanol ingestion on cytokine expression in the lung requires AC7 expression in myeloid cells. Thus, we hypothesize that AC7 plays a key role in regulating the effects of acute alcohol ingestion on the immune system. We postulate that acute ingestion of alcohol results in an increase in one or more Gs-coupled receptor agonist(s) either locally in the lung or systemically in circulation. This, in turn, stimulates AC7 activity in myeloid cells, such as alveolar macrophages, resulting in suppression of immune responses. In this proposal, we will utilize the myeloid lineage specific AC7 knockout mice. We will employ acute alcohol ingestion combined with live bacteria peritoneal injection to elucidate the mechanisms by which ethanol suppresses innate immune responses via AC7 activity. This is a well-established mouse model for acute lung injury induced by sepsis in humans. The Specific Aims of the proposal are Aim 1: To determine innate immune responses in the lung of the myeloid lineage specific AC7 knockout mice in response to bacterial infection and acute ethanol treatment and Aim 2: To quantify Gs-coupled receptor agonists in bronchoalveolar lavage fluid and plasma and cAMP levels in the lungs of animals treated with alcohol and live bacteria. We postulate that adenosine, adrenaline, and prostaglandin E2 are the prime candidates for Gs-coupled receptor agonists increasing by acute ethanol ingestion. The proposed study is concise and focused on acute alcohol effects on lung inflammation caused by bacterial infection. Results from the proposed studies will generate mechanistic information regarding the effects of alcohol on the immune system via AC7 activity. The data derived from this study will become a foundation for future research in which mechanistic aspects of alcohol effects on immune system are studied in detail and may lead to a pharmacological intervention to counter negative consequences of alcohol ingestion.