The antioxidant and antifibrogenic effects of the glycosaminoglycans hyaluronic acid and chondroitin-4-sulphate in a subchronic rat model of carbon tetrachloride-induced liver fibrogenesis.
Hepatic fibrosis involves the interplay of many factors including reactive oxygen species. Recent reports described antioxidant properties of glycosaminoglycans (GAGs). Since several findings have shown that hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S) may act as antioxidant molecules, the aim of this research was to evaluate the antioxidant effects of HYA and C4S treatment in a rat model of liver fibrosis. The effect on tissue inhibitors of metalloproteinases (TIMPs) was also studied. Liver fibrosis was induced in rats by eight intraperitoneal injections of CCl4, twice a week for 6 weeks. HYA or C4S alone (25 mg/kg) or HYA and C4S in combination (12.5 + 12.5 mg/kg) were administered daily by the same route during the 6 weeks. At the end of the 6-week treatment period (24 h after the last dose of GAGs), the following parameters were evaluated: (1) serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as index of hepatic cell disruption; (2) hepatic conjugated dienes (CD), as index of lipid peroxidation; (3) hepatic TIMPs activity and expression; (4) hepatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) activity, as index of endogenous defences; (5) hepatic hydroxyproline, as index of collagen deposition. CCl4-induced liver fibrosis enhanced lipid peroxidation and TIMPs activation, increased ALT and AST, depleted antioxidants SOD and GPx, and caused collagen deposition in liver tissue. Treatment with GAGs, especially when in combination, successfully reduced ALT and AST rise, lipid peroxidation by evaluating conjugated dienes, TIMPs activation and mRNA expression, partially restored SOD and GPx activities, and limited collagen deposition in the hepatic tissue. The data obtained showed that these molecules were able to limit hepatic injury induced by chronic CCl4 intoxication and especially limited liver fibrosis. They also confirm that HYA and C4S may exert antioxidant mechanism, while reduction of TIMPs expression suggests that GAGs may influence MMPs and TIMPs imbalance in liver fibrosis.
Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, 98125, Italy. gcampo@unime.it
Giuseppe M
GM
Campo
Angela
A
Avenoso
Salvatore
S
Campo
Angela
A
D'Ascola
Alida M
AM
Ferlazzo
Alberto
A
Calatroni
D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D000975:Antioxidants; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000008:administration & dosage; D002252:Carbon Tetrachloride Poisoning; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D006025:Glycosaminoglycans / Q000494:pharmacology; D006820:Hyaluronic Acid / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D006025:Glycosaminoglycans; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates; D003094:Collagen; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase