An investigation of potential healing effects of cromolyn sodium on experimental cholestasis

Background and Aim:Cholestasis produces hepatocellular injury, ductuler cell proliferation and fibrosis of liver parenchyma. Mast cells have been shown to play a role in various hepatobiliary diseases and mast cell numbers are markedly increased in advanced liver fibrosis. Although various mechanisms have been defined in the formation of cholestatic pruritus, pathogenesis of the pruritus is still unclear. In this study, we aimed to investigate the possible effects of cromolyn sodium, a mast cell stabilizer, on biochemical and histopathological potential healing effects in experimental cholestasis which is induced by common bile duct ligation in rats. We also aimed to investigate its efficacy on cholestatic pruritus and to compare the effectiveness with a group of therapeutic agents used in this area. Materials and Methods: Sixty-nine male rats of Spraque Dawley, weighing between 193-296 grams, were randomly divided into 8 groups. We weighed the rats preoperatively and applied the determined treatment every day consecutively for 10 days after the surgery. Common bile duct ligation (BDL) was not performed in the laparotomy sham group (n = 9) and no treatment was given. The control group (n=12) underwent common bile duct ligation and intraperitoneal (ip) saline solution was given as the treatment. Common bile duct ligation was applied to the other 6 groups. BDL+CROM group (n=9) received ip cromolyn sodium, BDL+CPM group (n=8) received ip chlorpheniramine maleate, BDL+SERT group (n=8) received oral sertraline, BDL+OND group (n=8) received ip ondansetron, BDL+UDCA group (n=7) received oral ursodeoxycholic acid and lastly BDL+NAL group (n=8) received ip naloxone. Fifth and tenth days of the experiment, subjects were observed for 5 minutes in terms of itching behavior. After 10 days, the rats were weighed and blood samples were taken under general anesthesia. Lastly, tissue (skin-subcutaneous, peritoneal membrane, liver) samples were taken for histopathological studies with sacrification. Results: A significant decrease was observed in biochemical parameters (serum histamine and autotaxin, plasma total bile acids, ALP, GGT, total and direct bilirubin levels) in the BDL+CROM group compared to the control group except for plasma AST and ALT values (p<0.05). The most number of parameters decreased significantly in the BDL+CROM group. When liver specimens were evaluated histopathologically, portal inflammation, lobular inflammation, bile duct proliferation, necrosis and fibrosis were significantly improved in BDL+CROM and BDL+SERT group compared to the control group (p<0.05). Liver, skin and peritoneal mast cells were increased by cholestasis. In the BDL+CROM group, liver and peritoneal mast cells were significantly decreased compared to the control group (p=0.003, p=0.004, respectively), whereas skin mast cells did not significantly decrease (p=0.09). On the fifth and tenth days of the experiment, the mean duration of rat's itching was significantly lower in all groups compared to the control group (p<0.05, p<0.05, respectively). Duration of the itching was observed to be increased in control, sham, BDL+OND and BDL+NAL groups from day 5 to 10 as it was decreased in BDL+CPM, BDL+SERT, BDL+UDCA and BDL+CROM groups. Conclusion: Our study showed that mast cell stabilizer cromolyn sodium, an untested agent in cholestatic pruritus has promising anti-pruritic efficacy and has provided biochemical and histopathological recovery in cholestasis. Keywords:Cholestasis, cholestatic pruritus, mast cells, cromolyn sodium, autotaxin