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 名酒精使用障碍患者患上败血症。与没有酗酒史的脓毒症患者相比，长期酗酒的脓毒症患者的死亡率和多器官功能障碍的严重程度增加。我们创建了一个小鼠模型，与没有酗酒史的败血症患者相比，酒精败血症患者的死亡率增加。虽然酒精喂养和水喂养的脓毒症小鼠的大多数器官相似，但我们发现酒精喂养的脓毒症小鼠的肠道完整性和免疫系统都严重失调。在比较酒精喂养的脓毒症小鼠和水喂养的脓毒症小鼠时出现了两个关键和互补的主题：1）肠道完整性和免疫反应的异常在酒精喂养的脓毒症小鼠中加剧，也许更重要的是，2）有许多似乎是脓毒症和长期饮酒相结合所特有的机制。具体而言，慢性酒精摄入和脓毒症的组合会出现多种异常，而慢性酒精摄入或脓毒症单独存在时则不会出现这种情况。该提案旨在通过检查肠道完整性（细胞凋亡、渗透性、增殖和绒毛长度）和宿主免疫反应（主要关注 CD4+ T 细胞和 NK 细胞）来了解这些机制。最后，该提案检查了肠道和免疫系统之间的串扰，试图了解改变肠道完整性如何改变宿主反应，以及改变免疫反应如何反过来改变酒精喂养的败血症小鼠的肠道完整性。由于患有酒精使用障碍的脓毒症宿主对脓毒症损伤的反应似乎与没有酗酒史的脓毒症宿主不同，因此这可能需要与“典型”脓毒症宿主不同的治疗方法。因此，了解慢性酒精摄入后脓毒症死亡的机制具有重要意义。 这种常见、昂贵且高度致命的疾病对健康的影响。