The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis

每年有100，000至250，000名酒精使用障碍患者出现败血症。脓毒症患者 与败血症相比，慢性酒精滥用增加了死亡率和多器官功能障碍的严重程度。 无酗酒史的患者。这项提案旨在了解为什么长期酗酒 败血症的结果，因为这种常见的-和致命的-情况是负责数千人死亡 这对美国的医疗保健系统构成了巨大的财政负担。在上一轮的调查中，我们 特征小鼠模型，复制酒精性脓毒症患者中观察到的死亡率增加， 没有酗酒史的败血症患者重要的是，虽然大多数器官 在酒精/脓毒症和水/脓毒症小鼠之间具有相似的功能和组织学， 酒精/败血症小鼠的免疫系统严重失调。这表现在两个互补性 的方式首先，在酒精/败血症小鼠中，肠道完整性和免疫反应的异常加剧 与水/脓毒症小鼠相比。其次，仅在酒精/脓毒症小鼠中发现了许多差异 酒精和败血症都不会单独出现。值得注意的是，肠通透性是 在酒精/败血症中恶化，这与肠道紧密连接的变化有关， 酒精和败血症的混合症状对共抑制受体CTLA-4的阻断也显著更多。 在酒精/脓毒症中比水/脓毒症有效，与调节性T细胞和效应细胞的差异相关 CD 4+细胞。最后，CD 43（与T细胞归巢和活化有关）的表达延迟。 酒精/脓毒症和存活率在脓毒症CD 43-/-小鼠中改变。该提案旨在了解 肠道渗透性和适应性免疫反应的这些特定差异背后的机制 酒精/败血症小鼠。由于患有酒精使用障碍的脓毒症宿主对脓毒症的反应似乎不同， 侮辱比那些没有酗酒史，这可能需要不同的治疗方法， 在“典型的”脓毒症宿主中是必需的。因此，这一提议将阐明肠道和 酒精/脓毒症期间的免疫功能障碍，最终目标是改善这种常见和 非常脆弱的人群。

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.