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用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究

林峰,  周志军,  张晨虹,  刘芳,  郭闻渊,  魏若菡,  陈慧

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文章导航 > 药学实践与服务  > 2014 >  32(2): 110-113,127
林峰, 周志军, 张晨虹, 刘芳, 郭闻渊, 魏若菡, 陈慧. 用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究[J]. 药学实践与服务, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
引用本文: 林峰, 周志军, 张晨虹, 刘芳, 郭闻渊, 魏若菡, 陈慧. 用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究[J]. 药学实践与服务, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
shu
LIN Feng, ZHOU Zhijun, ZHANG Chenhong, LIU Fang, GUO Wenyuan, WEI Ruohan, CHEN Hui. Alleviation of reperfusion injury for liver graft via inhibiting inflammatory response by ulinastatin[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
Citation: LIN Feng, ZHOU Zhijun, ZHANG Chenhong, LIU Fang, GUO Wenyuan, WEI Ruohan, CHEN Hui. Alleviation of reperfusion injury for liver graft via inhibiting inflammatory response by ulinastatin[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
shu

用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究

doi: 10.3969/j.issn.1006-0111.2014.02.009
  • 1.

    台州市第一人民医院, 浙江 台州 318020

  • 2.

    第二军医大学附属长征医院器官移植科, 上海 200003

基金项目: 上海市科委医学引导项目(114119a7900);浙江省台州市科技局项目(131ky15).

Alleviation of reperfusion injury for liver graft via inhibiting inflammatory response by ulinastatin

  • 1.

    The First People's Hospital of Taizhou, Taizhou 318020, China

  • 2.

    Organ Transplantation Center, Changzheng Hospital Afilliated to Second Military Medical University, Shanghai 200003, China

  • 摘要: 目的 研究乌司他丁(ulinastatin,UTI)对移植肝再灌注损伤的保护作用及相关机制。 方法 建立Sprague-Dawley同系大鼠肝移植(OLT)模型,受体分为3组,每组8只大鼠:假手术组、对照组和乌司他丁组。假手术组大鼠仅接受麻醉、开腹、肝周韧带游离及关腹操作;乌司他丁组及对照组大鼠建立OLT模型,门静脉开放后,乌司他丁组大鼠经尾静脉注射乌司他丁1×104 U/kg,对照组大鼠注射等量生理盐水。再灌注后6及24 h每组分别处死4只大鼠,获取下腔静脉血标本及肝脏标本。检测各组大鼠血清ALT水平及肝组织形态学变化、肝细胞凋亡情况;用免疫组化方法检测肝脏Kupffer细胞浸润,用荧光定量 RT-PCR检测肝脏肿瘤坏死因子(tumor necrosis factor, TNF)-α、白细胞介素(interleukin, IL)-6、IL-1β及单核细胞趋化蛋白(monocyte chemoattractant protein,MCP)-1mRNA表达水平,用酶联免疫吸附试验检测受体血清内上述炎症介质含量;用蛋白质印迹技术检测肝脏内核因子(nuclear factor, NF)-κB亚单位P65磷酸化水平。 结果 与对照组相比,在同一时点检测乌司他丁组大鼠血清ALT水平明显降低(P<0.01),肝脏组织学损伤情况明显改善(P<0.01),肝细胞凋亡明显减少(P<0.01);肝脏内TNF-α、IL-1β、IL-6、MCP-1的mRNA表达降低(P<0.01),血清内上述炎症介质含量明显降低(P<0.01);P65磷酸化水平明显下降。 结论 乌司他丁能够减轻大鼠移植肝再灌注损伤,其机制可能与其抑制再灌注后炎症反应有关。
    Abstract: Objective To evaluate the protective effect of ulinastatin on reperfusion injury of liver graft in rats and the related mechanisms. Methods The orthotopic liver transplantation (OLT) model between syngeneic Sprague-Dawley rats was used, and recipient rats were allocated in three groups:sham operation (SO) group, control group, and ulinastatin (UTI) group. Just after OLT procedure, rats in UTI group received ulinastatin injection at a dose of 1×104 IU/kg by tail vein, and rats in control group received saline injection with equal dose. Four rats at 6 hour and the others at 24 hour after OLT were sacrificed; the sera and liver were collected. The ALT levels in serum were detected and hepatic histological changes and hepatocellular apoptosis were examined. The infiltration of Kupffer cells was detected by immunochemistry analysis, and the relative mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and monocyte chemoattractant protein (MCP)-1 in the liver tissue and the content of these cytokines in the sera were measured with real time PCR and ELISA. The activation of transcription factor NF-κB was measured with Western blotting analysis. Results Compared with the rats in control group, at the same time-point rats in UTI group exhibited lower levels of ALT (P<0.01), better hepatic histological changes (P<0.01), less hepatocellular apoptosis (P<0.01), lower mRNA expression of TNF-α, IL-6, IL-1β and MCP-1 in the liver tissue and lower content of these cytokines in the sera (P<0.01). Moreover, the activation of NF-κB in UTI group was significantly down-regulated in comparison with that in control group. Conclusion Ulinastatin could reduce reperfusion injury for liver graft via inhibiting inflammatory response and deserve deep research as novel protective agent.
  • [1] Song S, Shen X, Tang Y, et al. Sinomenine pretreatment attenuates cold ischemia/reperfusion injury in rats:the role of heme oxygenase-1[J]. Int Immunopharmacol, 2010, 10(6):679.
    [2] Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method[J]. Methods, 2001, 25(4):402.
    [3] Suzuki S, Toledo-Pereyra LH, Rodriguez FJ, et al. Neutrophil infiltration as an important factor in liver ischemia and reperfusion injury. Modulating effects of FK506 and cyclosporine[J]. Transplantation,1993, 55(6):1265.
    [4] Dogan S, Aslan M. Hepatic ischemia-reperfusion injury and therapeutic strategies to alleviate cellular damage[J]. Hepatol Res,2011, 41(2):103.
    [5] Bhogal RH, Sutaria R, Afford SC. Hepatic liver ischemia/reperfusion injury:processes in inflammatory networks—a review[J]. Liver Transpl, 2011,17(1):95.
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    [8] 郑继海, 王金彩, 卢光洲. 乌司他丁与奥曲肽治疗急性胰腺炎的经济学评价[J].药学实践杂志, 2005, 23(2):103.
    [9] Hou J, Zhu MW, He XW, et al. Effect of hyperbaric oxygen and ulinastatin on plasma endotoxin, soluble CD14, endotoxin-neutralizing capacity and cytokines in acute necrotizing pancreatitis[J]. Can J Surg, 2010, 53(4):241.
    [10] Park KH, Lee KH, Kim H, et al. The anti-inflammatory effects of ulinastatin in trauma patients with hemorrhagic shock[J]. J Korean Med Sci, 2010, 25(1):128.
    [11] Wanner GA, Ertel W, Müller P, et al. Liver ischemia and reperfusion induces a systemic inflammatory response through Kupffer cell activation[J]. Shock,1996,5(1):34.
    [12] 郭闻渊, 滕飞, 宋少华, 等. 丹参多酚酸盐抑制库普弗细胞活化减轻肝脏再灌注损伤[J]. 上海医学, 2010, 33(7):644.
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  • 收稿日期:  2012-04-29
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用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究

doi: 10.3969/j.issn.1006-0111.2014.02.009
  • 1. 台州市第一人民医院, 浙江 台州 318020
  • 2. 第二军医大学附属长征医院器官移植科, 上海 200003
    • 基金项目:  上海市科委医学引导项目(114119a7900);浙江省台州市科技局项目(131ky15).
  • 收稿日期: 2012-04-29
  • 修回日期: 2013-04-17

摘要: 目的 研究乌司他丁(ulinastatin,UTI)对移植肝再灌注损伤的保护作用及相关机制。 方法 建立Sprague-Dawley同系大鼠肝移植(OLT)模型,受体分为3组,每组8只大鼠:假手术组、对照组和乌司他丁组。假手术组大鼠仅接受麻醉、开腹、肝周韧带游离及关腹操作;乌司他丁组及对照组大鼠建立OLT模型,门静脉开放后,乌司他丁组大鼠经尾静脉注射乌司他丁1×104 U/kg,对照组大鼠注射等量生理盐水。再灌注后6及24 h每组分别处死4只大鼠,获取下腔静脉血标本及肝脏标本。检测各组大鼠血清ALT水平及肝组织形态学变化、肝细胞凋亡情况;用免疫组化方法检测肝脏Kupffer细胞浸润,用荧光定量 RT-PCR检测肝脏肿瘤坏死因子(tumor necrosis factor, TNF)-α、白细胞介素(interleukin, IL)-6、IL-1β及单核细胞趋化蛋白(monocyte chemoattractant protein,MCP)-1mRNA表达水平,用酶联免疫吸附试验检测受体血清内上述炎症介质含量;用蛋白质印迹技术检测肝脏内核因子(nuclear factor, NF)-κB亚单位P65磷酸化水平。 结果 与对照组相比,在同一时点检测乌司他丁组大鼠血清ALT水平明显降低(P<0.01),肝脏组织学损伤情况明显改善(P<0.01),肝细胞凋亡明显减少(P<0.01);肝脏内TNF-α、IL-1β、IL-6、MCP-1的mRNA表达降低(P<0.01),血清内上述炎症介质含量明显降低(P<0.01);P65磷酸化水平明显下降。 结论 乌司他丁能够减轻大鼠移植肝再灌注损伤,其机制可能与其抑制再灌注后炎症反应有关。

English Abstract

林峰, 周志军, 张晨虹, 刘芳, 郭闻渊, 魏若菡, 陈慧. 用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究[J]. 药学实践与服务, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
引用本文: 林峰, 周志军, 张晨虹, 刘芳, 郭闻渊, 魏若菡, 陈慧. 用乌司他丁抑制炎症反应减轻大鼠移植肝再灌注损伤的实验研究[J]. 药学实践与服务, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
shu
LIN Feng, ZHOU Zhijun, ZHANG Chenhong, LIU Fang, GUO Wenyuan, WEI Ruohan, CHEN Hui. Alleviation of reperfusion injury for liver graft via inhibiting inflammatory response by ulinastatin[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
Citation: LIN Feng, ZHOU Zhijun, ZHANG Chenhong, LIU Fang, GUO Wenyuan, WEI Ruohan, CHEN Hui. Alleviation of reperfusion injury for liver graft via inhibiting inflammatory response by ulinastatin[J]. Journal of Pharmaceutical Practice and Service, 2014, 32(2): 110-113,127. doi: 10.3969/j.issn.1006-0111.2014.02.009
shu

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