Watanabe Kazuteru, Togo Shinji, Takahashi Takuji, Matsuyama Ryusei, Yamamoto Harumi, Shimizu Tetsuya, Makino Hirochika, Matsuo Kenichi, Morioka Daisuke, Kubota Toru, Nagashima Yoji, Shimada Hiroshi
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
J Surg Res. 2007 Nov;143(1):13-9. doi: 10.1016/j.jss.2007.04.041. Epub 2007 Jul 26.
BACKGROUND/AIMS: Well-organized turnover of the extracellular matrix is important in liver regeneration, which is regulated by the plasminogen activating system. The aim of this study was to investigate the role of plasminogen activator inhibitor-1 (PAI-1) after excessive hepatectomy and to ascertain whether angiotensin-converting enzyme (ACE) inhibitors, which are PAI-1 inhibitors as well, successfully improve the survival rate of rats that have undergone 95% partial hepatectomy (PHx).
Using liver tissues sampled after 90% or 95% PHx, the expression of PAI-1 mRNA was evaluated using reverse transcription polymerase chain reaction. Hepatic PAI-1 protein and urokinase-type plasminogen activator (uPA) levels were determined by enzyme-linked immunosorbent assay. Survival study and cytodynamic analysis by 5-bromo-2'-deoxyuridine staining were performed to evaluate the effects of ACE inhibition.
The levels of PAI-1 mRNA and hepatic PAI-1 protein in the 95% PHx group peaked and were then maintained. By contrast, the uPA level fell relative to the 90% PHx group. Additionally, the hepatic PAI-1 protein level decreased and the survival rate improved in the 95% PHx rats that had undergone ACE inhibition.
Our experimental results suggest that PAI-1 plays a role in the occurrence of liver failure after excessive hepatectomy via accelerated maturation of pro-uPA and fibrinolytic factors. These are potential molecular therapeutic targets for liver failure after excessive hepatectomy.
背景/目的：细胞外基质有序的更新在肝脏再生中很重要，其受纤溶酶原激活系统调控。本研究旨在探讨过量肝切除术后纤溶酶原激活物抑制剂-1（PAI-1）的作用，并确定同为PAI-1抑制剂的血管紧张素转换酶（ACE）抑制剂是否能成功提高接受95%部分肝切除术（PHx）大鼠的存活率。
使用90%或95% PHx术后采集的肝脏组织，采用逆转录聚合酶链反应评估PAI-1 mRNA的表达。通过酶联免疫吸附测定法测定肝脏PAI-1蛋白和尿激酶型纤溶酶原激活物（uPA）水平。进行生存研究和5-溴-2'-脱氧尿苷染色的细胞动力学分析以评估ACE抑制的效果。
95% PHx组中PAI-1 mRNA和肝脏PAI-1蛋白水平先达到峰值然后维持稳定。相比之下，与90% PHx组相比，uPA水平下降。此外，接受ACE抑制的95% PHx大鼠肝脏PAI-1蛋白水平降低且存活率提高。
我们的实验结果表明，PAI-1通过加速pro-uPA和纤溶因子的成熟在过量肝切除术后肝衰竭的发生中起作用。这些是过量肝切除术后肝衰竭潜在的分子治疗靶点。
