Hepatic Haemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and CIBERehd, University of Barcelona, Spain.
J Hepatol. 2013 Feb;58(2):240-6. doi: 10.1016/j.jhep.2012.09.010. Epub 2012 Sep 16.
BACKGROUND & AIMS: High oxidative stress plays a major role in increasing hepatic vascular resistance in cirrhosis, by facilitating liver fibrosis and by increasing hepatic vascular tone. This study is aimed at investigating whether the use of the novel isoform of recombinant human manganese superoxide dismutase (rMnSOD) could be a new therapeutic strategy to reduce oxidative stress and portal hypertension in cirrhotic rats.
In CCl(4)- and BDL-cirrhotic rats treated with rMnSOD (i.p. 15 μg/kg/day) or its vehicle for 7 days, mean arterial pressure (MAP), portal pressure (PP) and portal blood flow (PBF) or small mesenteric arterial flow (SMABF) were measured. In addition, in CCl(4)-cirrhotic rats, we evaluated the hepatic vasodilatory response to acetylcholine, liver fibrosis with Sirius red staining and hepatic stellate cell activation by α-smooth muscle actin (α-SMA) protein expression.
rMnSOD treatment significantly reduced PP either in CCl(4)- or BDL-cirrhotic rats without significant changes in splanchnic blood flow, suggesting a reduction in hepatic vascular resistance. MAP was not modified. Reduction in PP was associated with a significant reduction in liver fibrosis, and α-SMA protein expression as well as with improved vasodilatory response to acetylcholine.
Chronic rMnSOD administration to cirrhotic rats reduces portal pressure by reducing hepatic vascular resistance without deleterious effects on systemic hemodynamics, suggesting that it might constitute a new antioxidant to be considered as additional therapy for treating portal hypertension in cirrhosis.
在肝硬化中，高氧化应激通过促进肝纤维化和增加肝血管张力，在增加肝血管阻力方面起着主要作用。本研究旨在研究新型重组人锰超氧化物歧化酶（rMnSOD）是否可作为一种新的治疗策略，以降低肝硬化大鼠的氧化应激和门脉高压。
在接受 rMnSOD（腹腔内 15μg/kg/天）或其载体治疗 7 天的 CCl4-和 BDL-肝硬化大鼠中，测量平均动脉压（MAP）、门静脉压（PP）和门静脉血流量（PBF）或肠系膜小动脉血流量（SMABF）。此外，在 CCl4-肝硬化大鼠中，我们评估了肝对乙酰胆碱的血管舒张反应、天狼星红染色的肝纤维化和α-平滑肌肌动蛋白（α-SMA）蛋白表达的肝星状细胞活化。
rMnSOD 治疗显著降低了 CCl4-或 BDL-肝硬化大鼠的 PP，而对内脏血流无明显变化，提示肝血管阻力降低。MAP 没有改变。PP 的降低与肝纤维化的显著减少以及α-SMA 蛋白表达的减少以及对乙酰胆碱的血管舒张反应的改善相关。
慢性 rMnSOD 给药可降低肝硬化大鼠的门静脉压，而不损害全身血液动力学，提示其可能构成一种新的抗氧化剂，可作为治疗肝硬化门静脉高压的附加治疗方法。
