The Impact of Chronic Alcohol Abuse on the Pathophysiology of Sepsis

描述(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。与没有酒精滥用史的脓毒症患者相比，慢性酒精滥用的脓毒症患者的死亡率和多器官功能障碍的严重程度都有所增加。我们已经创建了一个小鼠模型，与没有酗酒史的脓毒症患者相比，酒精脓毒症患者的死亡率增加。虽然酒精喂养的脓毒症小鼠和水喂养的脓毒症小鼠的大部分器官相似，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且互补的主题：1)酒精喂养的脓毒症小鼠的肠道完整性和免疫反应的异常加剧，也许更重要的是，2)有许多机制似乎是脓毒症和慢性酒精使用相结合所特有的。具体地说，慢性酒精摄入和脓毒症的组合存在多种异常，而慢性酒精摄入或脓毒症单独不存在。该提案试图通过检查肠道完整性(细胞凋亡、通透性、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，以及反过来改变免疫反应如何改变酒精喂养的脓毒症小鼠的肠道完整性。由于有酒精使用障碍的败血症宿主对败血症侮辱的反应似乎与那些没有酗酒史的人不同，这可能需要一种不同于“典型”败血症宿主的治疗方法。因此，了解慢性酒精摄入后脓毒症的死亡机制具有重要的意义。 这种疾病很常见，代价很高，而且极具致命性，对健康有影响。

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.