Hori Tomohide, Uemoto Shinji, Chen Feng, Gardner Lindsay B, Baine Ann-Marie T, Hata Toshiyuki, Kogure Takayuki, Nguyen Justin H
Tomohide Hori, Shinji Uemoto, Division of Hepato-Biliary-Pancreatic and Transplant Surgery, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
World J Hepatol. 2014 Feb 27;6(2):72-84. doi: 10.4254/wjh.v6.i2.72.
To investigate oxidative stress (OS)-mediated damage and the behavior of extracellular matrices in various rat models because shear stress with portal hypertension and cold ischemia/warm reperfusion injury trigger the liver regeneration cascade after surgery. These injuries also cause fatal liver damage.
Rats were divided into four groups according to the surgery performed: control; hepatectomy with 40% liver remnant (60% hepatectomy); orthotopic liver transplantation (OLT) with whole liver graft (100% OLT); and split OLT (SOLT) with 40% graft (40% SOLT). Survival was evaluated. Blood and liver samples were collected at 6 h after surgery. Biochemical and histopathological examinations were performed. OS-induced damage, 4-hydroxynonenal, ataxia-telangiectasia mutated kinase, histone H2AX, phosphatidylinositol 3-kinase (PI3K) and Akt were evaluated by western blotting. Behavior of extracellular matrices, matrix metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were also evaluated by western blotting and zymography.
Although 100% OLT survived, 60% hepatectomy and 40% SOLT showed poor survival. Histopathological, immunohistological, biochemical and protein assays revealed that 60% hepatectomy, 100% OLT and 40% SOLT showed liver damage. PI3K and Akt were decreased in 60% hepatectomy and 40% SOLT. For protein expression, 40% SOLT showed differences in MMP-9, MMP-2 and TIMP-2. TIMP-1 showed differences in 60% hepatectomy and 40% SOLT. For protein activity, MMP-9 demonstrated significant differences in 60% hepatectomy, 100% OLT and 40% SOLT.
Under conditions with an insufficient liver remnant, prevention of OS-induced damage via the Akt/PI3K pathway may be key to improve the postoperative course. MMP-9 may be also a therapeutic target after surgery.
研究氧化应激（OS）介导的损伤以及细胞外基质在各种大鼠模型中的行为，因为门静脉高压引起的剪切应力和冷缺血/温再灌注损伤会触发术后肝脏再生级联反应。这些损伤也会导致致命的肝损伤。
根据所进行的手术将大鼠分为四组：对照组；保留40%肝脏的肝切除术（60%肝切除术）；全肝移植的原位肝移植（OLT，100%OLT）；以及40%移植肝的劈离式OLT（SOLT，40%SOLT）。评估存活率。术后6小时采集血液和肝脏样本。进行生化和组织病理学检查。通过蛋白质印迹法评估OS诱导的损伤、4-羟基壬烯醛、共济失调毛细血管扩张突变激酶、组蛋白H2AX、磷脂酰肌醇3-激酶（PI3K）和Akt。还通过蛋白质印迹法和酶谱法评估细胞外基质、基质金属蛋白酶（MMP）-9、MMP-2、金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2的行为。
尽管100%OLT组大鼠存活，但60%肝切除术组和40%SOLT组大鼠存活率较低。组织病理学、免疫组织化学、生化和蛋白质检测显示，6月肝切除术组、100%OLT组和|40%SOLT组出现肝损伤。60%肝切除术组和40%SOLT组中PI3K和Akt降低。在蛋白质表达方面，40%SOLT组在MMP-9、MMP-2和TIMP-2方面存在差异。TIMP-1在60%肝切除术组和40%SOLT组中存在差异。在蛋白质活性方面，MMP-9在60%肝切除术组、100%OLT组和40%SOLT组中表现出显著差异。
在肝脏残余量不足的情况下，通过Akt/PI3K途径预防OS诱导的损伤可能是改善术后病程的关键。MMP-9也可能是术后的治疗靶点。
