肝切除范围可调节转录因子的激活以及参与肝再生的细胞因子的产生。
Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration.
作者信息
Sowa Jan-Peter, Best Jan, Benko Tamas, Bockhorn Maximillian, Gu Yanli, Niehues Eva-Maria, Bucchi Agnieska, Benedetto-Castro Eva-Maria, Gerken Guido, Rauen Ursula, Schlaak Jorg-Friedrich
机构信息
Department of Gastroenterology and Hepatology, University Hospital of Essen, Hufelandstr. 55, 45122 Essen, Germany.
出版信息
World J Gastroenterol. 2008 Dec 14;14(46):7093-100. doi: 10.3748/wjg.14.7093.
AIM
To investigate the molecular events involved in liver regeneration following subtotal hepatectomy (SH) as previous studies have largely focused on partial hepatectomy (PH).
METHODS
Male Wistar rats were subjected to 70% PH or 90% SH, respectively, and sacrificed at different times after surgery. Untreated and sham-operated animals served as controls. Serum and liver samples were obtained to investigate liver function, apoptosis (TUNEL assay) and transcription factors (NF-kappaB, Stat3; ELISA) or cytokines (HGF, TNF-alpha, IL-6, TGF-alpha, TGF-beta; quantitative RT PCR) involved in liver regeneration.
RESULTS
Serum levels of ALT and AST in animals with 70% PH differed significantly from sham-operated and control animals. We found that the peak concentration 12 h after surgery returned to control levels 7 d after surgery. LDH was increased only at 12 h after 70% PH compared to sham. Bilirubin showed no differences between the sham and 70% resection. After PH, early NF-kappaB activation was detected 12 h after surgery (313.21 +/- 17.22 ng/mL), while there was no activation after SH (125.22 +/- 44.36 ng/mL) compared to controls (111.43 +/- 32.68 ng/mL) at this time point. In SH, however, NF-kappaB activation was delayed until 24 h (475.56 +/- 144.29 ng/mL). Stat3 activation was similar in both groups. These findings correlated with suppressed and delayed induction of regenerative genes after SH (i.e. TNF-alpha 24 h postoperatively: 2375 +/- 1220 in 70% and 88 +/- 31 in 90%; IL-6 12 h postoperatively: 2547 +/- 441 in 70% and 173 +/- 82 in 90%). TUNEL staining revealed elevated apoptosis rates in SH (0.44% at 24 h; 0.63% at 7 d) compared to PH (0.27% at 24 h; 0.15% at 7 d).
CONCLUSION
The molecular events involved in liver regeneration are significantly influenced by the extent of resection as SH leads to suppression and delay of liver regeneration compared to PH, which is associated with delayed activation of NF-kappaB and suppression of proregenerative cytokines.
目的
鉴于以往研究主要聚焦于部分肝切除术（PH），本研究旨在探究肝大部切除术（SH）后肝再生所涉及的分子事件。
方法
将雄性Wistar大鼠分别进行70%肝切除术或90%肝大部切除术，并在术后不同时间点处死。未处理及假手术动物作为对照。获取血清和肝脏样本以研究肝功能、凋亡（TUNEL检测）以及参与肝再生的转录因子（核因子κB、信号转导子和转录激活子3；酶联免疫吸附测定）或细胞因子（肝细胞生长因子、肿瘤坏死因子-α、白细胞介素-6、转化生长因子-α、转化生长因子-β；定量逆转录聚合酶链反应）。
结果
70%肝切除术组动物血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平与假手术组及对照组动物存在显著差异。我们发现术后12小时达到峰值浓度，术后7天恢复至对照水平。与假手术组相比，70%肝切除术后仅在12小时乳酸脱氢酶（LDH）升高。假手术组与70%切除组之间胆红素无差异。肝切除术后，术后12小时检测到早期核因子κB激活（313.21±17.22纳克/毫升），而此时肝大部切除术后与对照组（111.43±32.68纳克/毫升）相比无激活（125.22±44.36纳克/毫升）。然而，在肝大部切除术中，核因子κB激活延迟至24小时（475.56±144.29纳克/毫升）。两组中信号转导子和转录激活子3激活情况相似。这些发现与肝大部切除术后再生基因诱导的抑制和延迟相关（即术后24小时肿瘤坏死因子-α：70%肝切除术组为2375±1220，90%肝大部切除术组为88±31；术后12小时白细胞介素-6：70%肝切除术组为2547±441，90%肝大部切除术组为173±82）。TUNEL染色显示，与肝切除术相比，肝大部切除术组凋亡率升高（24小时时为0.44%；7天时为0.63%）（肝切除术组24小时时为0.27%；7天时为0.15%）。
结论
肝再生所涉及的分子事件受切除范围显著影响，因为与肝切除术相比，肝大部切除术导致肝再生受到抑制和延迟，这与核因子κB激活延迟及促再生细胞因子受抑制有关。
Zotero 插件