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

项目摘要/摘要 饮酒通过以下方式损害免疫防御系统的各个组成部分的功能 调节人类和动物模型的先天免疫和获得性免疫。然而，这些机制 乙醇对免疫系统的影响目前还不完全清楚。众所周知，循环 AMP(CAMP)调节免疫反应；然而，特定的腺酰环化酶(AC)亚型是否 主要负责调节乙醇对免疫反应的影响尚不清楚 下定决心。我们的长期目标是阐明a)哪种特定的AC异构体(S)调节(S)乙醇的 对免疫反应的影响，以及b)这种调节的机制。 使用髓系特异性7型AC异构体(AC7)基因敲除小鼠，我们的初步数据表明 急性酒精摄入对肺组织细胞因子表达的抑制作用需要AC7的表达 髓系细胞。因此，我们假设AC7在调节急性酒精的影响中起关键作用。 对免疫系统的摄取。我们推测，急性摄入酒精会导致一个或多个 更多的Gs偶联受体激动剂(S)局部在肺或全身循环中。这又反过来， 刺激髓系细胞，如肺泡巨噬细胞的AC7活性，导致免疫抑制 回应。在这个提案中，我们将利用髓系特异性AC7基因敲除小鼠。我们将使用急性 酒精摄入结合活菌腹腔注射阐明乙醇的作用机制 通过AC7活性抑制先天免疫反应。这是一个公认的急性肺病小鼠模型。 败血症对人类造成的伤害。该提案的具体目标是目标1：确定先天免疫 髓系特异性AC7基因敲除小鼠对细菌的肺部反应 感染和急性酒精治疗与目标2：定量检测G_s偶联受体激动剂 酒精染毒动物肺泡灌洗液、血浆和肺组织cAMP水平的变化 和活细菌。我们推测腺苷、肾上腺素和前列腺素E_2是 GS偶联受体激动剂因急性乙醇摄入而增加。建议的研究简明扼要，重点突出。 急性酒精对细菌感染所致肺部炎症的影响。拟议研究的结果 将通过AC7活动产生关于酒精对免疫系统影响的机械性信息。 从这项研究中获得的数据将成为未来研究的基础，在这些研究中， 酒精对免疫系统的影响进行了详细的研究，并可能导致药物干预以对抗 酒精摄入的负面后果。

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.