Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation
Mortality of Septic Mice Strongly Correlates With Adrenal Gland Inflammation
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DOI：
10.1097/ccm.0000000000001373
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发表时间：
2016-04-01
影响因子：
8.8
通讯作者：
Zacharowski, Kai
中科院分区：
文献类型：
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作者：
Jennewein, Carla;Nguyen Tran;Zacharowski, Kai
目的：脓毒症和脓毒性休克是ICU中常见的疾病，伴随着显著的发病率、死亡率和费用。脓毒症继发性肾上腺功能不全的发生率仍有争议，识别和适当治疗也是一个挑战。采用遗传或手术引发肾上腺功能不全的脓毒症动物模型导致死亡率增加，但其机制尚不清楚。本研究调查了盲肠结扎和穿孔对脓毒症小鼠肾上腺炎症的影响。设计：前瞻性实验研究。设置：大学实验室。受试者：C57 BL/6 N野生型小鼠。干预：盲肠结扎和穿孔诱导脓毒症24和48小时。测量和主要结果：对脓毒症小鼠和对照小鼠进行仔细监测（每30分钟一次）长达48小时，并将其分为存活小鼠和非存活小鼠。我们观察到，与假手术动物和存活动物相比，死亡动物肾上腺蛋白提取物中的白细胞介素-6、白细胞介素-1和肿瘤坏死因子-显著大量增加。这种模式部分反映在肝脏和肺中，但不在血浆样品中。值得注意的是，与存活者相比，死亡者中仅发现肺白细胞介素-6显著增加。与这些发现一致，我们在死亡小鼠的肾上腺中检测到更高程度的白细胞浸润和出血。对这些动物的下丘脑-垂体-肾上腺轴反应的评价显示促肾上腺皮质激素增加，这仅部分反映在皮质酮水平上。值得注意的是，使用促肾上腺皮质激素刺激试验，我们发现一个受损的促肾上腺皮质激素的反应，特别是在nonsurvivors，这显着相关的浸润leukocytes.Conclusions的数量：盲肠结扎和穿刺诱导的小鼠脓毒症诱导肾上腺，这是伴随着细胞死亡和出血强烈的炎症反应。我们的数据表明，死亡率和肾上腺失能与肾上腺炎症的程度有关，从而强调了肾上腺功能对生存的重要性。
Objectives: Sepsis and septic shock are commonly present in the ICU and accompanied by significant morbidity, mortality, and cost. The frequency of secondary adrenal insufficiency in sepsis remains open to debate and a challenge to identify and treat appropriately. Animal models of sepsis using genetic or surgical initiation of adrenal insufficiency resulted in increased mortality, but the mechanisms are still unclear. The present study investigates the impact of adrenal inflammation in septic mice challenged with cecal ligation and puncture.Design: Prospective experimental study.Setting: University laboratory.Subjects: C57BL/6N wild-type mice.Interventions: Sepsis, induced by cecal ligation and puncture for 24 and 48 hours.Measurements and Main Results: Both septic and control mice were carefully monitored (every 30 min) for up to 48 hours and divided into survivors and nonsurvivors. We observed a significant and massive increase of interleukin-6, interleukin-1, and tumor necrosis factor- in adrenal protein extracts of nonsurvivors compared with sham animals and survivors. This pattern was partly reflected in liver and lung but not in plasma samples. Notably, a significant increase in nonsurvivors compared with survivors was only found for lung interleukin-6. In line with these findings, we detected a higher degree of leukocyte infiltration and hemorrhage in the adrenal glands of deceased mice. Evaluation of the hypothalamic-pituitary-adrenal axis response in these animals revealed an increase of adrenocorticotropic hormone, which was only partly reflected in the corticosterone level. Notably, using the adrenocorticotropic hormone stimulation test, we found an impaired adrenocorticotropic hormone response, particularly in nonsurvivors, which significantly correlated with the number of infiltrated leukocytes.Conclusions: Cecal ligation and puncture-induced murine sepsis induces a strong inflammatory response in the adrenal glands, which is accompanied by cell death and hemorrhage. Our data suggest that mortality and adrenal incapacitation are associated with the degree of adrenal inflammation, thereby underscoring the importance of adrenal function on survival.