Olprinone Attenuates Excessive Shear Stress Through Up-Regulation of Endothelial Nitric Oxide Synthase in a Rat Excessive Hepatectomy Model
Olprinone Attenuates Excessive Shear Stress Through Up-Regulation of Endothelial Nitric Oxide Synthase in a Rat Excessive Hepatectomy Model
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DOI：
10.1002/lt.22189
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发表时间：
2011-01-01
影响因子：
4.6
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
--
作者：
Yamanaka, Kenya;Hatano, Etsuro;Uemoto, Shinji
扩大肝切除术后，残余肝脏中过大的切应力会导致术后肝衰竭。Olprinone（OLP）是一种选择性磷酸二酯酶III抑制剂，据报道可改善微循环和减轻炎症。本研究的目的是研究OLP对过度肝切除（EHx）大鼠模型切应力的影响。在本研究中，EHx包括刘易斯大鼠的90%肝切除术和左、右Glisson鞘结扎。在EHx前48小时用渗透泵腹腔内给予OLP或生理盐水。为了评估切应力，我们测量了门静脉（PV）压力。我们还通过免疫组织化学和电子显微镜评估了窦状隙内皮细胞的损伤。此外，我们评估了细胞凋亡在肝脏与末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记法。用OLP处理上调肝内皮型一氧化氮合酶（eNOS）表达。在结扎后30分钟内，OLP处理的大鼠中由于Glisson鞘结扎引起的PV压力增加减弱。用OLP治疗保留了肝窦内皮细胞，减少了残肝的凋亡。OLP治疗组大鼠的生存概率显著优于对照组（33.3% vs 13.3%）。OLP组大鼠术后eNOS活性明显高于对照组。对OLP处理的大鼠给予NO-硝基-L-精氨酸甲酯消除了OLP对EHx后PV压力和存活率的影响。因此，我们得出结论，OLP通过上调eNOS来减弱过度的切应力，并提高EHx后的存活率。肝移植17：60-69，2011. (C)2011年AASLD。2010年6月9日接收; 2010年9月9日接受。
After extended hepatectomy, excessive shear stress in the remnant liver causes postoperative liver failure. Olprinone (OLP), a selective phosphodiesterase III inhibitor, has been reported to improve microcirculation and attenuate inflammation. The aim of this study was to investigate the effects of OLP on shear stress in rats with an excessive hepatectomy (EHx) model. In this study, EHx comprised 90% hepatectomy with ligation of the left and right Glisson's sheaths in Lewis rats. OLP or saline was intraperitoneally administered with an osmotic pump 48 hours before EHx. To evaluate the shear stress, we measured the portal vein (PV) pressure. We also assessed sinusoidal endothelial cell injury by immunohistochemistry and electron microscopy. Furthermore, we assessed apoptosis in the liver with the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick-end labeling method. Treatment with OLP up-regulated hepatic endothelial nitric oxide synthase (eNOS) expression. The increase in the PV pressure due to Glisson's sheath ligation was attenuated in OLP-treated rats during a 30-minute period after ligation. Treatment with OLP preserved sinusoidal endothelial cells and reduced apoptosis in the remnant liver. The probability of survival in the OLP-treated rats was significantly better than that in the controls (33.3% versus 13.3%). Furthermore, the postoperative eNOS activity in the OLP-treated rats was higher than that in the controls. The administration of No-nitro-l-arginine methyl ester to OLP-treated rats eliminated the effects of OLP on PV pressure and survival after EHx. Therefore, we concluded that OLP attenuates excessive shear stress through the up-regulation of eNOS and improves the survival rate after EHx. Liver Transpl 17:60-69, 2011. (C) 2011 AASLD. Received June 9, 2010; accepted September 9, 2010.