The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis

长期酗酒对脓毒症病理生理学的影响

• 批准号: 8662516
• 负责人: Craig M Coopersmith
• 金额: $ 29.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662516
• 关键词: Alcohol abuse; Alcohol consumption; Alcohols; Animals; Apoptosis; Bilateral; CD4 Positive T Lymphocytes; Chronic; Communities; Critical Illness; Data; Disease; Etiology; Frequencies; Functional disorder; Goals; Immune; Immune response; Immune system; Interferons; Length; Ligation; Modeling; Multiple Abnormalities; Mus; Natural Killer Cells; Operative Surgical Procedures; Organ; Outcome; Pathology; Patients; Pattern; Permeability; Population; Prevalence; Production; Public Health; Publishing; Puncture procedure; Recording of previous events; Sepsis; Severities; TNF gene; Therapeutic; Time; Tissues; United States; Villus; Water; alcohol abuse therapy; alcohol use disorder; chronic alcohol ingestion; cytokine; feeding; immune function; improved; mortality; occludin; problem drinker; public health relevance; research study; septic

DESCRIPTION (provided by applicant): Over 100,000 patients with alcohol use disorders develop sepsis annually. Septic patients with chronic alcohol abuse have increased mortality and severity of multiple organ dysfunction compared to septic patients without a history of alcohol abuse. We have created a murine model that replicates the increased mortality seen in alcoholic septic patients compared to patients who develop sepsis without a history of alcohol abuse. While the majority of organs are similar between alcohol-fed and water-fed septic mice, we found that both gut integrity and the immune system are severely dysregulated in alcohol-fed septic mice. Two key and complementary themes emerged in comparing alcohol-fed septic mice and water-fed septic mice: 1) abnormalities in gut integrity and the immune response are exacerbated in alcohol-fed septic mice and perhaps more importantly, 2) there are a number of mechanisms that appear to be specific to the combination of sepsis and chronic alcohol usage. Specifically, multiple abnormalities are present with the combination of chronic alcohol ingestion and sepsis that are not present with either chronic alcohol ingestion or sepsis in isolation. The proposal seeks to understand these mechanisms by examining both gut integrity (apoptosis, permeability, proliferation, and villus length) and the host immune response (primarily focusing on CD4+ T cells and NK cells). Finally, the proposal examines crosstalk between the gut and the immune system, seeking to understand how changing gut integrity alters the host response and reciprocally how altering the immune response changes gut integrity in alcohol-fed septic mice. Since septic hosts with alcohol use disorders appear to respond differently to a septic insult than those without a history of alcohol abuse, this may require a different therapeutic approach than would be needed in a "typical" septic host. Understanding the mechanisms underlying mortality in sepsis following chronic alcohol ingestion therefore has significant public health implications in a disease that is common, very costly, and highly lethal.

描述（由申请人提供）：每年有超过100,000多名酒精使用障碍患者出现败血症。与没有酒精滥用病史相比，慢性酒精滥用的化粪池患者的死亡率和多个器官功能障碍的严重程度增加。我们创建了一个鼠模型，与没有酗酒史的败血症患者相比，酒精化粪池患者的死亡率增加。虽然大多数器官在酒精喂养和水喂养的化粪池小鼠之间相似，但我们发现肠道完整性和免疫系统在酒精喂养的化粪池小鼠中严重失调。在比较酒精喂养的化粪池和水喂养的化粪池小鼠时出现了两个关键和互补主题：1）肠道完整性异常和免疫反应在酒精喂养的化粪池小鼠中加剧了，更重要的是，2）似乎有许多机制，这些机制似乎是特定的，这些机制似乎是sepis and sepis and sepis and Chronenconcis and chornorconic and compiss and parcessis and consepis and consepis and consecis and consecis and consecis的组合。具体而言，存在多种异常，与慢性酒精摄入或分离出败血症的慢性酒精摄入和败血症的结合在一起。该提案试图通过检查肠道完整性（凋亡，渗透率，增殖和绒毛长度）和宿主免疫反应（主要集中于CD4+ T细胞和NK细胞）来理解这些机制。最后，该提案研究了肠道与免疫系统之间的串扰，试图了解肠道的变化如何改变宿主反应，并相互改变免疫反应如何改变酒精喂养的化粪池中的肠道完整性。由于具有饮酒障碍的化粪池宿主对化粪池侮辱的反应与没有酒精滥用病史的侮辱的反应不同，因此这可能需要与“典型”化粪池宿主所需的治疗方法不同。因此，了解慢性酒精摄入后败血症的死亡率的机制，因此有很大的公众 对这种常见，非常昂贵且高度致命的疾病的健康影响。