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

Abstract

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Maeva Guillaume, Aina Rodriguez-Vilarrupla, Jorge Gracia-Sancho, Eugenio Rosado, Aldo Mancini, Jaume Bosch, Joan Carles Garcia-Pagán
• Journal: Journal of hepatology (J Hepatol) Vol. 58 Issue 2 Pg. 240-6 (Feb 2013) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22989570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Recombinant Proteins
• Carbon Tetrachloride
• Superoxide Dismutase

Topics

• Animals
• Carbon Tetrachloride (adverse effects)
• Disease Models, Animal
• Hypertension, Portal (drug therapy, etiology, physiopathology)
• Liver Cirrhosis (chemically induced, complications, drug therapy, etiology, pathology)
• Male
• Oxidative Stress (drug effects, physiology)
• Portal Pressure (drug effects, physiology)
• Rats
• Rats, Wistar
• Recombinant Proteins (pharmacology, therapeutic use)
• Superoxide Dismutase (pharmacology, therapeutic use)
• Treatment Outcome
• Vascular Resistance (drug effects, physiology)