Atividade biológica do condroitim sulfato nos estágios iniciais de colestase extra-hepática

Abstract

Chondroitin sulfate (CS) is a glycosaminoglycan (GAG) present in the extracellular matrix (ECM) of many mammalian tissue, used for osteoarthritis treatment and, recently, has aroused great interest due to its anti-inflammatory potential. Several in vivo inflammation experimental models are employed to study anti-inflammatory activity, including extra-hepatic cholestasis induced fibrosis. Cholestasis produces hepatocellular injury with portal tract edema, leukocyte infiltration, biliary epithelial cells proliferation and portal tract fibrosis. The aim of this work was to analyze CS effects on an extra-hepatic cholestasis experimental model induced by bile duct ligation (BDL) on Wistar rats. For this purpose 6 to 8 weeks old animals (n = 82) were euthanized 2, 7 or 14 days after surgical procedure, previously divided into groups: BDL, CS treated BDL, Sham, CS treated Sham. To analyze disease evolution body and liver weight, serum concentrations of direct bilirubin (BD), globulins, activities of gamma glutamyl transferase (Gama GT), alkaline phosphatase (FA), alanine and aspartate aminotransferases (ALT and AST), morphological changes on tissue, mieloperoxidase (MPO) activity, matrix metalloproteinases (MMP-9, pró MMP-2 and MMP-2) activities and liver GAGs content, besides histopathological analysis of the tissue. CS acquired presented over 92% tenor, molecular weight of approximately 40 kDa and disaccharide content of Δdi4S predominantly (65%).BDL caused many symptoms related to cellular damage and inflammatory process such as increasing BD and globulins, elevation of Gama GT, FA, ALT and AST activities, inflammatory infiltrate and changes on liver morphometry, with ductular proliferation, and on the ECM. CS reduced initial burst on aminotransferases, indicating protection of tissues injured on surgery procedure. Treatment led to reduction of inflammatory infiltrate, showed by significant decreasing on MPO activity. Tissue remodeling was also reduced, with decrease of MMP-9, pro MMP-2 and MMP-2 activities and also of GAGs dermatam sulfate and heparam sulfate levels, produced by hepatic stellate cells in response of tissue damage. These results show that CS reduced cholestasis hepatic injury effects, being capable to slow down liver fibrogenesis.