Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6-/- mice
Sepsis-induced cholestasis, steatosis, hepatocellular injury, and impaired hepatocellular regeneration are enhanced in interleukin-6-/- mice
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DOI：
10.1097/01.ccm.0000240229.98275.07
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发表时间：
2006-10-01
影响因子：
8.8
通讯作者：
Raj, Nichelle R.
中科院分区：
文献类型：
--
作者：
Deutschman, Clifford S.;Cereda, Maurizio;Raj, Nichelle R.
目标。肝功能障碍是脓毒症的一个重要但鲜为人知的组成部分。在严重脓毒症中，肝功能障碍的特征是胆汁淤积、脂肪变性、肝细胞损伤、再生受损、对细胞因子白介素-6的反应降低和高死亡率。为了确定白细胞介素-6活性的丧失是否会导致肝功能障碍和死亡率，我们在野生型（白细胞介素-6 +/+）和白细胞介素-6敲除（白细胞介素-6 -/-）小鼠中诱导败血症。我们假设白细胞介素-6 -/-小鼠的败血症会增加胆汁淤积、脂肪变性、肝细胞损伤和死亡率，并损害肝细胞再生。设计：随机前瞻性实验研究。大学医学实验室。男性青少年C57BI6介素-6 +/+和介素-6 -/-小鼠。干预措施。采用盲肠结扎单次穿刺（CLP）诱导轻度脓毒症。采用盲肠结扎双穿刺（2CLP）诱导严重致死性脓毒症。一些小鼠在CLP/ 2CLP时接受重组人白细胞介素-6。所有动物在手术时和手术后每24小时进行一次液体复苏。在存活组中，记录16、24、48和72小时的死亡率。在不同的队列中，存活的动物在24和48小时时被杀死，并收获肝脏组织。另一组小鼠接受溴脱氧尿苷检测再生。测量和主要结果：2CLP在白细胞介素-6 -/-小鼠的头12小时内死亡率为100%。白细胞介素-6 +/+小鼠24小时前2CLP死亡率为零，72小时时为90%。72小时时，白细胞介素-6 +/+小鼠的CLP致死率为40%，而白细胞介素-6 -/-小鼠的致死率为90%。CLP在白细胞介素-6 -/-而非白细胞介素-6 +/+小鼠中诱导胆汁淤积、脂肪变性和肝细胞损伤。在白细胞介素-6 -/-的动物中，CLP后没有再生，但在白细胞介素-6 +/+的小鼠中出现了再生。早期给药重组人白细胞介素-6不能逆转白细胞介素-6 -/-小鼠的异常。白细胞介素-6的缺乏是脓毒症患者肝功能障碍和死亡率的重要决定因素。
Objective. Hepatic dysfunction is an important but poorly understood component of sepsis. In severe sepsis, liver dysfunction is characterized by cholestasis, steatosis, hepatocellular injury, impaired regeneration, a decreased response to the cytokine interleukin-6, and high mortality. To determine whether loss of interleukin-6 activity caused hepatic dysfunction and mortality, we induced sepsis in wild-type (interleukin-6 +/+) and interleukin-6 knockout (interieukin-6 -/-) mice. We hypothesized that sepsis in interleukin-6 -/- mice would increase cholestasis, steatosis, hepatocellular injury, and mortality and impair hepatocyte regeneration.Design: Randomized prospective experimental study.Setting. University medical laboratory.Subjects. Male adolescent C57BI6 interieukin-6 +/+ and interieukin-6 -/- mice.Interventions. Mild sepsis was induced using cecal ligation and single puncture (CLP). Severe, lethal sepsis was induced using cecal ligation and double puncture (2CLP). Some mice received recombinant human interleukin-6 at the time of CLP/ 2CLP. All animals were fluid resuscitated at the time of surgery and every 24 hrs thereafter. In survival cohorts, mortality at 16, 24, 48, and 72 hrs was recorded. In separate cohorts, surviving animals were killed at 24 and 48 hrs, and liver tissue was harvested. A separate cohort of mice received bromodeoxyuridine for detection of regeneration.Measurements and Main Results: 2CLP was 100% fatal within the first 12 hrs in interleukin-6 -/- mice. Mortality from 2CLP in interieukin-6 +/+ mice before 24 hrs was nil but was 90% by 72 hrs. At 72 hrs, CLP was 40% fatal in interieukin-6 +/+ mice but 90% in interleukin-6 -/- mice. CLP induced cholestasis, steatosis, and hepatocellular injury in interieukin-6 -/-, but not interleukin-6 +/+, mice. Regeneration was absent following CLP in interleukin-6 -/- animals but occurred in interleukin-6 +/+ mice. Early administration of recombinant human interleukin-6 did not reverse abnormalities in interleukin-6 -/- mice.Conclusions. The absence of interleukin-6 is an important determinant of hepatic dysfunction and mortality in sepsis.