Recombinant human manganese superoxide dismutase reduces liver fibrosis and portal pressure in CCl4 cirrhotic rats

Purpose. High oxidative stress within the cirrhotic liver plays a major role in increasing hepatic vascular resistance, the primary factor in the development of portal hypertension, and does so by facilitating liver fibrosis and increasing hepatic vascular tone. We aimed to investigate whether use of the novel isoform of recombinant human manganese superoxide dismutase (rMnSOD), which has the particular property of entering cells and exhibiting a potent intra and extracellular antioxidant activity, could be a new therapeutic strategy to reduce portal hypertension in CCl4 cirrhotic (CH) rats.Methods. After treating CH rats with rMnSOD (i.p. 15 µg/kg/day, n = 11) or its vehicle (n = 9) for sept days, mean arterial pressure (MAP), portal pressure (PP) and portal blood flow (PBF) were measured. The vasodilatory response to acetylcholine was evaluated in isolated perfused livers preconstricted with 0.1 M methoxamine, with liver sections being stained for fibrosis (Sirius red) and for hepatic stellate cell activation (a-smooth muscle actin). Results. rMnSOD treatment significantly reduced PP (mean decrease 14 %) without significant changes in PBF, reflecting decreased hepatic vascular resistance. MAP was not modified. These effects were associated with a significant reduction in Sirius red staining and a-smooth muscle actin expression, as well as with improved vasodilatory response to acetylcholine. Conclusions. Chronic rMnSOD administration reduces portal pressure, intrahepatic vascular resistance and liver fibrosis and improves hepatic endothelial dysfunction in cirrhotic rats, suggesting that it might constitute a new antioxidant to be considered as additional therapy for treating portal hypertension in cirrhosis.