Theodorakis Nicholas G, Wang Yining N, Wu Jianmin, Maluccio Mary A, Skill Nicholas J
Indiana University, Department of Surgery Indianapolis, IN, 46202, USA.
Int J Physiol Pathophysiol Pharmacol. 2010 Mar 8;2(2):104-110.
The cytokine tumor necrosis factor alpha (TNFa) has previously been identified in the development of portal hypertension (PHT) by facilitating portal venous and systemic hyperemia. TNFa is reported to contribute to hyperemia via endothelial nitric oxide synthase (eNOS) induction and nitric oxide (NO) production. This study examines this hypothesis by utilizing TNFa receptor knockout mice and a murine model of pre-hepatic PHT. Plasma TNFa and NOx and tissue TNFa mRNA levels were determined in wild-type mice 0-7d post induction of pre-hepatic PHT by partial portal vein ligation (PVL). TNFa receptor knockout mice also received PVL or sham surgery and splenic pulp pressure, abdominal aortic flow and portal-systemic shunting were recorded 7d following. Portal pressure and systemic hyperemia developed rapidly following PVL. Plasma NOx was increased temporarily 2-3 days following PVL and returned to baseline by day 7. Circulating TNFa was below detectable limits of the ELISA used, as such no increase was observed. Hepatic and vascular TNFa mRNA levels were transiently changed after PVL otherwise there was no significant change. TNFa receptor targeted gene deletion did not ameliorate plasma NOx following PVL and had no effect on the development of PHT. TNFa receptor signaling plays no detectable role in the development of systemic hyperemia in the murine model of pre-hepatic PHT. Consequently, increased TNFa observed in intra-hepatic inflammatory models (CCl(4)) and in patients is probably related to inflammation associated with intra-hepatic pathology. Alternatively, TNFa may be signaling via a TNFa receptor independent mechanism.
细胞因子肿瘤坏死因子α（TNFα）先前已被确定通过促进门静脉和全身充血参与门静脉高压症（PHT）的发展。据报道，TNFα通过诱导内皮型一氧化氮合酶（eNOS）和产生一氧化氮（NO）来促进充血。本研究通过使用TNFα受体敲除小鼠和肝前性PHT的小鼠模型来检验这一假设。在通过部分门静脉结扎（PVL）诱导肝前性PHT后0-7天，测定野生型小鼠的血浆TNFα、NOx和组织TNFα mRNA水平。TNFα受体敲除小鼠也接受PVL或假手术，并在7天后记录脾髓压、腹主动脉血流和门体分流情况。PVL后门静脉压力和全身充血迅速发展。PVL后2-3天血浆NOx暂时升高，到第7天恢复到基线水平。循环中的TNFα低于所用ELISA的检测限，因此未观察到升高。PVL后肝脏和血管TNFα mRNA水平短暂变化，否则无显著变化。TNFα受体靶向基因缺失并未改善PVL后的血浆NOx，对PHT的发展也无影响。在肝前性PHT小鼠模型中，TNFα受体信号传导在全身充血的发展中未发挥可检测到的作用。因此，在肝内炎症模型（CCl₄）和患者中观察到的TNFα增加可能与肝内病理相关的炎症有关。或者说，TNFα可能通过一种不依赖TNFα受体的机制进行信号传导。
