Hepatic damage in biliary-obstructed rats is ameliorated by leflunomide treatment

Abstract

Cholestasis, or impaired bile flow, occurs in a wide variety of liver diseases and causes hepatic damage by retention and accumulation of toxic hydrophobic bile salts inducing persistent inflammation and oxidative stress. In the present research, we studied the effect of leflunomide, a novel immunosuppressive and anti-inflammatory agent against autoimmune disease, on hepatic damage produced by double ligature of the extrahepatic biliary duct in Wistar Albino rats. Cholestasis was done by double ligature and section of the extrahepatic biliary duct (BDL). Leflunomide was given i.g. 10 mg/kg/day. The severity of cholestasis and hepatic injury was determined by changes in the plasma enzyme activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and levels of direct bilirubin. Malondialdehyde (MDA), protein carbonyl (PC), nitric oxide (NO), catalase (CAT) and superoxide dismutase (SOD) were determined to the oxidative status in the liver tissue. Myeloperoxidase (MPO) activity and levels of tissue hydroxyproline (HPR) were determined to neutrophil activation and collagen accumulation, respectively. Further, histological changes were studied. Treatment with leflunomide markedly reduced serum transaminase activities as compared to BDL rats. At the same time leflunomide significantly inhibited increases in liver MDA, PC and NO levels and also attenuated the depletion of CAT and SOD in the liver after bile duct ligation. Similarly, increase in tissue MPO activity and HPR due to BDL was also attenuated by leflunomide treatment. These findings were supported by histopathological findings. These findings suggested that leflunomide can attenuate hepatic damage in extrahepatic cholestasis by prevention of oxidative stress and inflammatory process.

Does leflunomide attenuate the sepsis-induced acute lung injury?

“…There is limited information related to antioxidant properties of leflunomide. Karaman et al reported that leflunomide increased the SOD and CAT activity during liver ischemia-reperfusion and biliary obstruction in rats [28,29]. In light of these results, we thought that leflunomide prevented the consumption of antioxidant enzymes by decreasing production of ROS via inhibition of neutrophils accumulation.…”

Protective Effect Of Curcumin On Liver Damage Induced By Biliary Obstruction In Rats

“…BDL is associated with the development of oxidant injury, hepatic fibrosis, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation that is a dynamic process implying different rates of progres- sion or regression (18). It has been reported that BDL reduces antioxidant defences and increases free radical formation (19). Some studies have suggested the role of free radicals in the modulation of hepatic fibrogenesis, either directly or through lipid peroxidation (20).…”

“…Biliary fibrosis is the result of initial hepatocyte injury, with a complex interaction among the inflamatory cells, platelets, Kupffer cells, cytokines and growth factors (21). The cytokines and growth factors are in close relation with oxygen free radicals and inflammation leading to the fibrosis (17,19). In this study, the changes demonstrating bile duct proliferation and fibrosis in expanded portal tracts, including the extension of proliferated bile ducts into lobules, mononuclear cells, and neutrophil infiltration into the widened portal areas, were observed in the BDL group.…”

Protective Effect of Naringin against Pylorus Ligation-induced Esophagitis in Male Wistar Rats

“…The enzyme CAT is also most abundant in liver, which catalyses the conversion of H 2 O 2 to corresponding oxygen and water. This enzyme action is reduced due to the presence of peroxides and reactive oxygen species [22] . Increase in concentration of H 2 O 2 in naringintreated groups depicted that there was higher amount of CAT enzyme available in the tissue to decompose the H 2 O 2 with respect to esophagitis control.…”