Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction.
Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction.
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DOI：
10.1097/hc9.0000000000000210
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发表时间：
2023-09-01
影响因子：
5.1
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中科院分区：
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随着重症监护实践的发展，脓毒症幸存者群体继续扩大，通常在许多器官（包括肝脏）中存在挥之不去的炎症。鉴于NAFLD患者人群的同时增加，在本研究中，我们旨在了解脓毒症对既存NAFLD和高血糖症的长期影响。将雄性小鼠随机分配至高脂肪饮食或对照饮食（CD）。饮食24周后，用肺炎克雷伯氏菌（Kpa）接种小鼠。在感染前1周和感染后2周和6周进行系列葡萄糖耐量试验、胰岛素和丙酮酸激发试验。对肝脏进行全组织RNA测序和组织学评价。为了测试持续性炎症是否可以在其他异常的肝脏环境中重现，小鼠在暴露于甲硫氨酸胆碱缺乏的高脂肪饮食后也用Kpa进行了攻击。最后，对65，139例患者的回顾性队列进行了分析，以评估肥胖是否与脓毒症后的肝损伤相关。接种Kpa后，高脂饮食小鼠的空腹血糖正常化，胰岛素敏感性没有变化，但丙酮酸利用率显著降低。肝脏检查显示局灶性巨噬细胞聚集和RNA分析的独特炎症基因特征。在临床队列中，肥胖前期、1级和2级肥胖与脓毒症后1-2年转氨酶水平升高的几率增加相关。在小鼠模型中，饮食诱导的肥胖和肺脓毒症存活的组合导致了肝脏新生和肝脏炎症的独特变化，与良性脂肪变性向脂肪性肝炎的进展一致。在一项队列研究中，肥胖患者脓毒症后1-2年转氨酶水平升高的风险增加。
As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline–deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1–2 years after sepsis. The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1–2 years following sepsis.