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: 10560545
• 负责人: Craig M Coopersmith
• 金额: $ 35.1万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560545
• 关键词: Adaptive Immune System; Affect; Alcohol abuse; Alcohol consumption; Alcohols; Animals; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CTLA4 blockade; CTLA4 gene; Cessation of life; Charge; Chronic; Data; Diagnosis; Diameter; Disease; Epidermal Growth Factor; Exhibits; FOXP3 gene; Financial Hardship; Frequencies; Functional disorder; Funding; Genetic; Goals; Healthcare Systems; Histology; Homing; Hour; Immune System Diseases; Immune response; Immune system; Intensive Care Units; Interleukin-12; Intestinal permeability; JAM protein; Modeling; Mus; Organ; Outcome; Pathway interactions; Patient Admission; Patients; Permeability; Persons; Proteins; Pseudomonas aeruginosa pneumonia; Recording of previous events; Regulatory T-Lymphocyte; Role; Sepsis; Septic Shock; Severities; Surface; T cell regulation; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Time; United States; Up-Regulation; Vulnerable Populations; Water; adaptive immune response; alcohol exposure; alcohol use disorder; cecal ligation puncture; cell type; chronic alcohol ingestion; comorbidity; cost; effector T cell; improved outcome; in vivo; mortality; mortality risk; mouse model; occludin; problem drinker; receptor; septic; septic patients; targeted treatment

Between 100,000 and 250,000 patients with alcohol use disorder 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. This proposal aims to understand why chronic alcohol abuse worsens outcomes in sepsis, as this common -- and deadly -- scenario is responsible for thousands of deaths per year and poses a huge financial burden on the U.S. healthcare system. In the previous cycle of finding, we characterized murine models that replicate the increased mortality seen in alcoholic septic patients compared to patients who develop sepsis without a history of alcohol abuse. Importantly, while the majority of organs have similar function and histology between alcohol/septic and water/septic mice, both gut integrity and the immune system are severely dysregulated in alcohol/septic mice. This is manifested in two complementary ways. First, abnormalities in gut integrity and the immune response are exacerbated in alcohol/septic mice compared to water/septic mice. Second, there are a number of differences identified only in alcohol/septic mice that are not present with either alcohol in isolation or sepsis in isolation. Notably, intestinal permeability is worsened in alcohol/sepsis, and this is associated with changes in the gut tight junction that are specific to the combination of alcohol and sepsis. Blockade of the co-inhibitory receptor CTLA-4 is also significantly more efficacious in alcohol/sepsis than water/sepsis, associated with differences in regulatory T cells and effector CD4+ cells. Finally, CD43 (which is implicated in T cell homing and activation) expression is delayed in alcohol/sepsis and survival is altered in septic CD43-/- mice. The proposal seeks to understand the mechanisms underlying these specific differences in gut permeability and the adaptive immune response in alcohol/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. As such, this proposal will elucidate mechanisms underlying gut and immune dysfunction during alcohol/sepsis with the ultimate goal of improving outcomes in this common and very vulnerable population.

每年有100,000至250,000例酒精使用障碍患者败血症患者。化粪池患者 与化粪池相比 没有酗酒病史的患者。该建议旨在了解为什么慢性酒精滥用 败血症的结果恶化，因为这种常见和致命的情况是数千人死亡的造成 每年，对美国医疗保健系统造成了巨大的财务燃烧。在上一个发现的周期中，我们 表征了复制酒精化粪池患者死亡率增加的鼠模型 对于没有酗酒史的败血症的患者。重要的是，大多数器官 酒精/化粪池和水/化粪池小鼠的功能和组织学相似，肠道完整性和 免疫系统在酒精/化粪池小鼠中严重失调。这在两个完善中表现出来 方式。首先，肠道完整性和免疫激发的异常在酒精/化粪池小鼠中加剧 与水/化粪池小鼠相比。其次，仅在酒精/化粪池小鼠中发现许多差异 孤立的酒精或败血症不存在。值得注意的是，肠渗透性是 酒精/败血症恶化，这与特定于肠道紧密连接的变化有关 酒精和败血症的结合。封闭受体CTLA-4的封锁也明显更多 与水/败血症相比，在酒精/败血症中有效，与调节性T细胞和效应子的差异有关 CD4+细胞。最后，CD43（在T细胞归巢和激活中暗示）的表达延迟 在败血症CD43 - / - 小鼠中，酒精/败血症和存活率改变。该提议试图了解 在肠道渗透性和适应性免疫响应中的这些特定差异的基础机制 酒精/化粪池小鼠。由于化粪池宿主患有饮酒障碍，对化粪池的反应不同 侮辱比没有酗酒史的侮辱，这可能需要采取不同的治疗方法 在“典型”化粪池宿主中需要。因此，该提案将阐明肠道和 酒精/败血症期间的免疫功能障碍，其最终目的是改善这种常见的结果和 非常脆弱的人口。

项目成果

Impact of chronic alcohol exposure on conventional and regulatory murine T cell subsets.

慢性酒精暴露对常规和调节性小鼠 T 细胞亚群的影响。

• DOI: 10.3389/fimmu.2023.1142614
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Paterson, Cameron W.;Gutierrez, Melissa B.;Coopersmith, Craig M.;Ford, Mandy L.
• 通讯作者: Ford, Mandy L.

Balancing Inflammation: The Link between Th17 and Regulatory T Cells.

• DOI: 10.1155/2016/6309219
• 发表时间: 2016
• 期刊: Mediators of inflammation
• 影响因子: 4.6
• 作者: Diller ML;Kudchadkar RR;Delman KA;Lawson DH;Ford ML
• 通讯作者: Ford ML