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

AC7 和酒精在细菌感染期间先天免疫反应中的作用

• 批准号: 10494203
• 负责人: Masami Yoshimura
• 金额: $ 7.26万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10494203
• 关键词: Acute; Adenosine; Adenylate Cyclase; Aftercare; Agonist; Alcohol consumption; Alcohols; Alveolar Macrophages; Animal Model; Animals; Autoimmune Diseases; Bacteria; Bacterial Infections; Blood Circulation; Bronchoalveolar Lavage Fluid; Cells; Chronic Disease; Coupled; Cyclic AMP; Data; Dinoprostone; Disease; Epinephrine; Escherichia coli; Ethanol; Foundations; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Goals; Health; Human; Immune; Immune response; Immune system; Immunoassay; Immunosuppression; In Vitro; Incidence; Infection; Infiltration; Inflammatory; Injections; Injury; Innate Immune Response; Intervention; Intraperitoneal Injections; Knock-out; Knockout Mice; Lead; Lung; Mediating; Messenger RNA; Myelogenous; Myeloid Cells; Natural Immunity; Nerve Degeneration; Oral; Peritoneal; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Protein Isoforms; Pulmonary Inflammation; Recovery; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Structure of parenchyma of lung; System; Systems Analysis; Therapeutic Intervention; Tissues; Traumatic injury; Virus; adaptive immunity; alcohol consequences; alcohol effect; base; chemokine; chronic alcohol ingestion; cytokine; economic cost; human model; mouse model; negative affect; neuroinflammation; receptor; response; sepsis induced acute lung injury; socioeconomics; Acute; Adenosine; Adenylate Cyclase; Aftercare; Agonist; Alcohol consumption; Alcohols; Alveolar Macrophages; Animal Model; Animals; Autoimmune Diseases; Bacteria; Bacterial Infections; Blood Circulation; Bronchoalveolar Lavage Fluid; Cells; Chronic Disease; Coupled; Cyclic AMP; Data; Dinoprostone; Disease; Epinephrine; Escherichia coli; Ethanol; Foundations; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Generations; Goals; Health; Human; Immune; Immune response; Immune system; Immunoassay; Immunosuppression; In Vitro; Incidence; Infection; Infiltration; Inflammatory; Injections; Injury; Innate Immune Response; Intervention; Intraperitoneal Injections; Knock-out; Knockout Mice; Lead; Lung; Mediating; Messenger RNA; Myelogenous; Myeloid Cells; Natural Immunity; Nerve Degeneration; Oral; Peritoneal; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Plasma; Play; Protein Isoforms; Pulmonary Inflammation; Recovery; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Structure of parenchyma of lung; System; Systems Analysis; Therapeutic Intervention; Tissues; Traumatic injury; Virus; adaptive immunity; alcohol consequences; alcohol effect; base; chemokine; chronic alcohol ingestion; cytokine; economic cost; human model; mouse model; negative affect; neuroinflammation; receptor; response; sepsis induced acute lung injury; socioeconomics

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.

项目摘要/摘要 饮酒损害了免疫防御系统各个组件的功能 调节人类和动物模型中的先天和适应性免疫。但是，机制 负责乙醇对免疫系统的影响，尚未完全理解。循环确定 AMP（CAMP）调节免疫反应；但是，特定的腺苷酸环化酶（AC）同工型是否为 首先负责调解乙醇对免疫反应的影响 决定。我们的长期目标是阐明a）AC调节的特定亚型的特定亚型 对免疫反应的影响，b）该调节的基础机制。 使用髓样谱系特异性7 AC同工型（AC7）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在 髓样细胞。这是我们假设AC7在调节急性酒精的影响中起关键作用 摄入免疫系统。我们假设急性摄入酒精会导致一个或 更多的GS耦合受体激动剂（S）在肺部或全身循环中。这又 刺激髓样细胞中的AC7活性，例如肺泡巨噬细胞，导致免疫抑制 回答。在此提案中，我们将利用髓样谱系特定的AC7敲除小鼠。我们将采用急性 酒精摄入与活细菌结合腹膜注射，以阐明乙醇的机制 通过AC7活性抑制先天免疫反应。这是急性肺的公认小鼠模型 败血症在人类中引起的伤害。提案的具体目的是目标1：确定先天免疫 对细菌的反应 感染和急性乙醇处理和目标2：量化GS耦合受体激动剂 用酒精治疗的动物的肺中的支气管肺泡灌洗液和血浆以及cAMP水平 和活细菌。我们假设腺苷，肾上腺素和前列腺素E2是主要候选人 GS耦合受体激动剂随着急性乙醇摄入而增加。拟议的研究是简洁而专注的 关于急性酒精对细菌感染引起的肺部感染的影响。拟议研究的结果 将通过AC7活性生成有关酒精对免疫系统影响的机械信息。 从这项研究中得出的数据将成为未来研究的基础 酒精对免疫系统的影响详细研究了，可能会导致药物干预以对抗 饮酒的负面后果。