Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and CD8+ T Cell Function After Pseudomonas Aeruginosa Pneumonia-Induced Sepsis.
Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and CD8+ T Cell Function After Pseudomonas Aeruginosa Pneumonia-Induced Sepsis.
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DOI：
10.1097/shk.0000000000001163
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发表时间：
2019-04
期刊：
影响因子：
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通讯作者：
Coopersmith CM
中科院分区：
文献类型：
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作者：
Klingensmith NJ;Fay KT;Lyons JD;Chen CW;Otani S;Liang Z;Chihade DB;Burd EM;Ford ML;Coopersmith CM
有酒精使用障碍史的脓毒症患者的死亡率高于无慢性酒精使用史的脓毒症患者。我们之前描述了一种慢性酒精摄入后盲肠结扎和穿刺导致败血症的模型，其中酒精喂养的脓毒症小鼠比水喂养的脓毒症小鼠死亡率更高，这与肠道完整性改变和脾脏CD4+ T细胞产生TNF和IFNγ的增加有关，而CD8+ T细胞功能没有改变。本研究的目的是通过建立一种新的模型来确定这是否代表了一种共同的宿主对酒精和败血症的反应，在这种模型中，慢性酒精摄入的小鼠遭受了不同的败血症模型。C57Bl/6小鼠随机接受酒精或水治疗12周，然后进行铜绿假单胞菌肺炎治疗。小鼠在脓毒症发作24小时后被处死，或被随访存活。酒精喂养的脓毒症小鼠的7天死亡率明显高于水喂养的脓毒症小鼠（96% vs 58%）。这与酒精喂养的败血症动物肠道凋亡增加5倍有关，并伴有促凋亡蛋白Bax的增加。酒精喂养的脓毒症小鼠血清IL-6水平升高，IL-2水平降低。相比之下，酒精喂养小鼠的CD8+ T细胞频率低于水喂养的脓毒症小鼠，这与刺激的脾细胞中IFNγ和TNF的产生增加有关。CD4+ T细胞、肺损伤、菌血症无显著性差异。因此，长期饮酒的小鼠死亡率增加，与肠道和免疫系统的变化无关。
Mortality is higher in septic patients with a history of alcohol use disorder than in septic patients without a history of chronic alcohol usage. We have previously described a model of chronic alcohol ingestion followed by sepsis from cecal ligation and puncture in which alcohol-fed septic mice have higher mortality than water-fed septic mice, associated with altered gut integrity and increased production of TNF and IFNγ by splenic CD4+ T cells without alterations in CD8+ T cell function. The purpose of this study was to determine whether this represents a common host response to the combination of alcohol and sepsis by creating a new model in which mice with chronic alcohol ingestion were subjected to a different model of sepsis. C57Bl/6 mice were randomized to receive either alcohol or water for 12 weeks and then subjected to Pseudomonas aeruginosa pneumonia. Mice were sacrificed either 24 hours after the onset of sepsis or followed for survival. Alcohol-fed septic mice had significantly higher 7-day mortality than water-fed septic mice (96% vs 58%). This was associated with a 5-fold increase in intestinal apoptosis in alcohol-fed septic animals, accompanied by an increase in the pro-apoptotic protein Bax. Serum IL-6 levels were higher and IL-2 levels were lower in alcohol-fed septic mice. In contrast, CD8+ T cell frequency was lower in alcohol-fed mice than water-fed septic mice, associated with increased production of IFNγ and TNF in stimulated splenocytes. No significant differences were noted in CD4+ T cells, lung injury or bacteremia. Mice with chronic alcohol ingestion thus have increased mortality regardless of their septic insult, associated with changes in both the gut and the immune system.