Catecholamines induce an inflammatory response in human hepatocytes
Catecholamines induce an inflammatory response in human hepatocytes
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DOI：
10.1097/ccm.0b013e31816532be
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发表时间：
2008-03-01
影响因子：
8.8
通讯作者：
Guillouzo, Andre
中科院分区：
文献类型：
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作者：
Aninat, Caroline;Seguin, Philippe;Guillouzo, Andre
Objective.肝脏是脓毒症、严重脓毒症和脓毒性休克的早期靶器官，导致多器官衰竭，脂多糖和肠源性儿茶酚胺都与肝细胞功能障碍的发生有关。感染性休克的治疗包括给予血管活性剂，如外源性儿茶酚胺或加压素，以恢复血压。作为临床应用的前奏，我们测试的假设，儿茶酚胺可以调节脂多糖诱导的炎症反应和功能在humanliver.Design：在体外人类细胞培养研究。设置.学术机构的研究实验室。干预：将原代人肝细胞和人肝癌HepaRG细胞暴露于脂多糖以评估肾上腺素和几种其他化合物（去甲肾上腺素、多巴酚丁胺、多巴胺、多培沙明、苯乙哌啶、可乐定、沙丁胺醇和加压素）的作用。分析了炎症标志物（白细胞介素-6、C-反应蛋白）和药物代谢标志物（细胞色素P450 [CYP] 3A 4、CYP 2B 6、CYP 1A 2、CYP 2 E1、组成型雄烷受体、甾烷X受体）。测量和主要结果。用10 ng/mL脂多糖处理24小时后，C反应蛋白和CYP 3A 4的转录分别强烈增加和抑制。与任一种儿茶酚胺的共治疗未能逆转脂多糖的作用，而单独添加时，肾上腺素，并在较小程度上去甲肾上腺素，沙丁胺醇和多巴酚丁胺醇，模仿脂多糖的作用。CYP 3A 4的抑制涉及β-肾上腺素能受体，并通过白细胞介素-6的过度产生介导。相比之下，加压素并没有引起炎症反应或修改CYP 3A 4 expression.Conclusions：一些儿茶酚胺可以诱导炎症反应，并加剧在脓毒症期间观察到的肝功能障碍，有利于这样的想法，即儿茶酚胺可以改变代谢的药物的生物转化CYP 3A 4和替代血管活性药物，如加压素，值得进一步研究在脓毒性休克患者。
Objective. The liver is an early target organ in sepsis, severe sepsis, and septic shock, contributing to multiple organ failure, and both lipopolysaccharide and gut-derived catecholamines are implicated in the occurrence of hepatocellular dysfunction. Treatment of septic shock involves administration of vasoactive agents such as exogenous catecholamines or vasopressin in order to reestablish blood pressure. As a prelude to clinical application, we tested the hypothesis that catecholamines could modulate the lipopolysaccharide-induced inflammatory response and function in human liver.Design: An in vitro human cell culture study. Setting. Research laboratory of an academic institution.Subjects. Primary human hepatocytes and human hepatoma HepaRG cells.Interventions: Primary human hepatocytes and human hepatoma HepaRG cells were exposed to lipopolysaccharide to evaluate effects of epinephrine and several other compounds (norepinephrine, dobutamine, dopamine, dopexamine, phenylephrine, clonidine, salbutamol, and vasopressin). Markers of inflammation (interieukin-6, C-reactive protein) and drug metabolism (cytochrome P450 [CYP] 3A4, CYP2B6, CYP1A2, CYP2E1, constitutive androstane receptor, pregnane X receptor) were analyzed. Measurements and Main Results. Transcripts of C-reactive protein and CYP3A4 were strongly increased and depressed respectively after a 24-hr treatment with 10 ng/mL lipopolysaccharide. Co-treatment with either of the catecholamines failed to reverse lipopolysaccharide effects, whereas when added alone, epinephrine, and to a lesser extent norepinephrine, salbutamol, and dobutamine, mimicked lipopolysaccharide effects. Suppression of CYP3A4 implicated beta-adrenergic receptors and was mediated through overproduction of interieukin-6. By contrast, vasopressin did not elicit an inflammatory response or modify CYP3A4 expression.Conclusions: Some catecholamines can induce an inflammatory response and exacerbate the hepatic dysfunction observed during sepsis, favoring the idea that catecholamines could alter the biotransformation of drugs metabolized by CYP3A4 and that alternative vasoactive agents, such as vasopressin, merit further investigation in septic shock patients.