terlipressin对肝大部切除术后早期小体积肝功能保护机制的研究
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孙亚冬 E-mail:sdongdong11@yahoo

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A preliminary study of protective mechanisms of terlipressin on small-for-size livers in the early posthepatectomy |phase
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    摘要:

    目的:探讨特利加压素(terlipressin)对大鼠肝切除术后早期残余肝脏功能的保护作用及其机制。
    方法:建立肝大部切除(90%)术后小体积肝大鼠动物模型,将60只模型大鼠随机分为:特利加压素治疗组(T组)30只及生理盐水对照组(C组)30只。两组大鼠均分别在肝门阻断下行肝切除残肝复流后30 min,2,4,6,24 h 5个时点进行观察。即每组分为5个亚组:T1/2,T2,T4,T6,T24及C1/2,C2,C4,C6,C24。每亚组6只大鼠。将两组所有时点血清标本进行ALT、AST及TBIL测定。活体肝组织冷冻标本用于半定量RT-PCR检测mRNA水平残肝内A20及iNOS基因的表达。肝组织石蜡切片用于HE染色光镜下观察形态学改变;免疫组化法检测ET-1,A20及iNOS的细胞内表达以及TUNEL法原位检测凋亡细胞。
    结果:两组ALT,AST及TBIL在再灌注后24h达高峰,其中T6及T24上述3个指标检测值明显低于C6和C24,(P<0.01)。RT-PCR结果显示,T2亚组较C2亚组 A20表达明显上调(P<0.05),C2亚组iNOS表达较T2亚组明显上调(P<0.05)。镜下观察T组肝组织在再灌注后各个时点形态学改变较C组轻微;C24肝组织见血管上皮细胞脱落、片状坏死、汇管区淋巴细胞侵润,而T24肝小叶结构保持尚完整,肝细胞及汇管区形态学特征基本正常。C6凋亡指数明显高于T6,(P<0.05)。免疫组化显示,T组各亚组A20表达均呈强阳性,2 h达高峰,T2,T4,T6  3个亚组A20表达均强于C组相应时点各亚组;T组及C组各时点亚组ET-1均有明显上调,T24 ET-1表达明显低于C24(P<0.05); T24亚组 iNOS表达较C24明显下调(P<0.05)。
    结论:terlipressin不仅对肝大部切除术后小体积肝功能具有保护作用,可预防肝功能进行性损害,改善预后,还能改善残肝再灌注后早期炎性反应及减少肝细胞凋亡;通过减轻肝窦机械性损伤,维持微循环稳定。

    Abstract:

    Objective:To explore the protective mechanisms of terlipressin on small-for-size livers in the early phase after major hepatectomy.
    Methods:The rat model of major hepatectomy(90%) with Pringle maneuver for 30 minutes was used for the study. A total of 60 rats were randomly categorized into 2 groups: Thirty rats in group T(Terlipressin group) and 30 in group C(control group). Five observation time points of 30min, 2h, 4h, 6h and 24h posthepatectomy after reperfusion were designed. A total of 10 subgroups, which were named T1/2, T2, T4, T6,T24 and C1/2, C2, C4, C6, C24 in terms of different time points and groups, were studied. Every subgroup consisted of 6 rats. Samples were collected from every subgroup. Blood samples were obtained for alanine transaminase, aspartate transaminase and total bilirubin  determination. Fresh frozen specimens of remnant liver were collected for RT-PCR detection of intrahepatic A20 and iNOS expression at mRNA levels. Paraffin sections of remnant liver were used for HE staining and then observed for morphological changes microscopically. Intracellular expression of endothelin-1(ET-1), A20 and iNOS were detected by histochemical staining. In situ cell death by TUNEL was also used for detection of apoptosis.
    Results:AST, ALT and TBil reached their peak levels at 24 hours after reperfusion in each group.The above 3 parameters were significantly reduced in subgroup T6 and T24 compared to subgroup C6 and C24 (all P<0.01). RT-PCR showed that except the time point of 30min after reperfusion, A20 expression was upregulated at all of the other time points in group Ts, overexpression was observed in subgroup T2 compared to group C(P<0.05). The expression of iNOS was down-regulated in group Ts as detected by RT-PCR; and on the contrary, it was upregulated in group Cs, overexpression was observed in sub group C2 compared to group T2 (P<0.05). Microscopic observation showed that the morphological changes of remnant liver in group T at every time point was markedly milder than that in group C. The apoptosis index in subgroup C6 was significantly higher than that in subgroup T6(P<0.05). Histochemical staining showed that A20 expression was stronger at subgroup T2,T4 and T6 compared to subgroup C2,C4 and C6.There was no marked difference of A20 expression at 24h after reperfusion in both groups. ET-1  was markedly down-regulated in subgroup T24 compared to C24(P<0.05). The iNOS expression was down-regulated in subgroup T24 compared to subgroup C24(P<0.05).
    Conclusions:Terlipressin can effectively improve small-for-size liver function in the early posthepatectomy phase after reperfusion. It can also inhibit the early inflammatory response. Hepatocyte apoptosis is attenuated by terlipressin. Terlipressin is also supposed to ameliorate sinusoidal mechanical injury and hence, to help stabilize microcirculatory homeostasis.

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任祖海|叶启发|余伟平|黄文鹏|陈晚平|邢晓为|蒋胜军|孙亚冬. terlipressin对肝大部切除术后早期小体积肝功能保护机制的研究[J].中国普通外科杂志,2010,19(7):756-762.
DOI:10.7659/j. issn.1005-6947.2010.07.010

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  • 收稿日期:2009-05-21
  • 最后修改日期:2010-01-18
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  • 在线发布日期: 2010-07-15