chondroitin-sulfates and Pancreatitis

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants such as danaparoid sodium (DA) may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesized that DA would act as an inhibitor of inflammation and prevent cerulein-induced acute pancreatitis. Male Wistar rats were used as subjects in this study. Each received a bolus of 50 U/kg of DA or saline-injected into the tail vein, followed by 4 injections of 50 mg/kg cerulean (i.p.) at 1-h intervals. Cytokine (IL-6), NO, and HMGB1 levels in serum and pancreatic tissue were measured after the cerulein injection. Pancreas histopathology and wet-dry ratio significantly improved in the DA-injected (50 U/kg) animals compared with saline-injected rats. Serum and pancreatic HMGB1 levels decreased over time in DA-treated animals. Danaparoid sodium also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, DA ameliorated pancreas pathology in the rat model of cerulein-induced acute pancreatitis. This study demonstrates that DA treatment prevents cerulein-induced acute pancreatitis in a rat model. This effect may be mediated through inhibition of cytokines, NO, and HMGB1.

Topics: Animals; Blotting, Western; Ceruletide; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Heparitin Sulfate; HMGB1 Protein; Immunohistochemistry; Interleukin-6; Male; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Pancreas; Pancreatitis; Peroxidase; Rats

Activation of nuclear factor kappaB (NF-kappaB) and caspases may greatly amplify inflammation and cell damage in addition to that directly exerted by free radicals. Since reactive oxygen species (ROS) are involved in acute pancreatitis, we studied whether the administration of chondroitin-4-sulphate (C4S), in addition to its antioxidant activity, was able to modulate NF-kappaB and caspase activation in an experimental model of caerulein-induced acute pancreatitis in mice. Hyperstimulating doses of caerulein (50 microg/ kg), five injections per mouse given at hourly intervals produced the following: high serum lipase and amylase activity; lipid peroxidation, evaluated by 8-isoprostane concentrations; loss of antioxidant defenses such as glutathione reductase (GR) activity; NF-kappaB activation and loss of cytoplasmic IkappaBalpha protein; increases in tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), caspase-3, and caspase-7 gene expression and their related protein; accumulation and activation of neutrophils in the damaged tissue, evaluated by elastase (ELA) determination; and pancreatic injury, evaluated by histologic analysis. Pretreatment of mice with different doses of C4S, given 1 hr before caerulein injections and 1 and 2 hrs after the last caerulein injection, reduced lipid peroxidation, inhibited NF-kappaB translocation and cytoplasmic IkappaBalpha protein loss, decreased TNF-alpha, IL-6, and caspase gene expression and their related protein levels, limited endogenous antioxidant depletion, and reduced tissue neutrophils accumulation and tissue damage. Since molecules with antioxidant activity can block NF-kappaB and apoptosis activation, we suggest that C4S administration is able to block NF-kappaB and caspase activation by reducing the oxidative burst.

Topics: Animals; Apoptosis; Ceruletide; Chondroitin Sulfates; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Glutathione Reductase; Interleukin-6; Lipase; Male; Mice; NF-kappa B; Oxidative Stress; Pancreatitis; Tumor Necrosis Factor-alpha

Several reports have described a loss of endogenous antioxidants and molecular oxidative damage during acute pancreatitis. Since hyaluronic acid and chondroitin-4-sulfate possess antioxidant properties, the effect of the administration of these glycosaminoglycans in a cerulein-induced acute pancreatitis in rats was investigated. Cerulein administration produced pancreatic edema and a marked increase in serum lipase and amylase activity; induced a severe depletion of reduced glutathione, catalase, and superoxide dismutase levels; primed lipid peroxidation; and promoted neutrophil intervention. Intraperitoneal pretreatment of rats with hyaluronic acid or chondroitin-4-sulfate or with both compounds ameliorated pancreatic cell conditions; restored the endogenous antioxidants reduced glutathione, catalase and superoxide dismutase; limited cell membrane peroxidation; and reduced neutrophil activation. Our data confirm the antioxidant activity of these 2 glycosaminoglycans.

Topics: Acute Disease; Amylases; Animals; Antioxidants; Chondroitin Sulfates; Edema; Hyaluronic Acid; Lipase; Male; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley