The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis

每年有10万至25万酒精使用障碍患者患上败血症。患有败血症的患者 与脓毒症相比，长期酗酒增加了死亡率和多器官功能障碍的严重性 没有酗酒史的患者。这项提案旨在了解为什么长期酗酒 恶化败血症的结局，因为这种常见且致命的情况导致数千人死亡 并给美国的医疗保健系统带来了巨大的财政负担。在之前的发现周期中，我们 复制酒精中毒性败血症患者死亡率增加的特征性小鼠模型的比较 适用于无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，两者的肠道完整性和 酒精/败血症小鼠的免疫系统严重失调。这体现在两个互补的方面 方式。首先，酒精/败血症小鼠的肠道完整性和免疫反应的异常加剧。 与水/败血症小鼠相比。其次，只在酒精/败血症小鼠身上发现了一些差异。 隔离时既不含酒精也不含败血症。值得注意的是，肠道通透性是 在酒精/败血症中恶化，这与肠道紧密连接的变化有关，这种变化是 酒精和败血症的结合。共抑制受体CTLA-4的阻断也明显更多 酒精/脓毒症比水/脓毒症有效，与调节性T细胞和效应器的差异有关 CD4细胞。最后，CD43(与T细胞归巢和激活有关)的表达被推迟 酒精/败血症和CD43-/-败血症小鼠的存活率发生改变。该提案试图理解 肠道通透性和获得性免疫反应的这些特殊差异背后的机制 酒精/败血症小鼠。因为有酒精使用障碍的败血症宿主对败血症的反应似乎不同 与那些没有酗酒史的人相比，这可能需要不同的治疗方法 是“典型”败血症宿主所需要的。因此，这项提议将阐明肠道和脑损伤的潜在机制 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.