Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats
Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats
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DOI：
10.1097/00024382-200014020-00017
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发表时间：
2000-08-01
期刊：
影响因子：
3.1
通讯作者：
Deutschman, CS
中科院分区：
文献类型：
--
作者：
Kim, PK;Chen, J;Deutschman, CS
脓毒症的肝功能障碍以高胆红素血症和肝内胆汁淤积为特征。我们假设脓毒症导致胆汁酸转运体牛磺胆酸钠协同转运体（Ntcp）和有机阴离子转运体多药耐药相关蛋白（Mrp 2）的肝转录降低，白细胞介素（IL）-6在下调Ntcp和Mrp 2表达中起重要作用。采用盲肠结扎单穿刺法（CLP）和盲肠结扎双穿刺法（2CLP）分别诱导SD大鼠轻度、非致死性脓毒症和暴发性脓毒症，CLP或2CLP后肝组织Ntcp和Mrp 2转录水平迅速下降。72小时后，CLP中的转录是基线的60%，2CLP中的转录是基线的14%。血清胆红素从24小时开始升高，在2CLP后24、48和72小时在固定的肝脏标本上观察到胆汁淤积，但CLP后未观察到。稳态Ntcp和Mrp 2 mRNA在IL-6处理的培养肝细胞和正常大鼠静脉注射1 mg/kg IL-6中降低。我们得出结论：1）Ntcp和Mrp 2转录在CLP后短暂下调，在2CLP后持续下调; 2）2CLP导致高胆红素血症和胆汁淤积，部分原因是Ntcp和Mrp 2转录持续下降; 3）改变的Ntcp和Mrp 2转录部分由IL-6介导。
Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP), Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.