Protective effect of febuxostat in sepsis-induced liver and kidney injuries after cecal ligation and puncture with the impact of xanthine oxidase, interleukin 1β, and c-Jun N-terminal kinases.

Abstract

Sepsis is one of the most common causes of death among hospitalized patients. Activity of xanthine oxidase (XO), a reactive oxygen species-producing enzyme, is known to be elevated in septic patients. Our aim was to investigate the possible protective role of XO inhibitor, febuxostat (FEB), in a rat model of sepsis-induced liver and kidney injures. Adult male albino rats were divided into four groups (n = 12 each): sham control, sham + FEB, cecal ligation and puncture (CLP), and CLP + FEB groups. FEB (10 mg/kg per os (p.o.)) was given once daily for 2 days and 30 min prior to laparotomy with CLP. CLP was associated with a high mortality rate accompanied by significant liver and kidney injuries indicated by elevated serum alanine aminotransferase, aspartate aminotransferase, urea, and creatinine levels and confirmed by histopathological tissue injury. Moreover, there was an increase in neutrophil gelatinase-associated lipocalin, uric acid, malondialdehyde, and nitric oxide levels and with decreased superoxide dismutase activity and total antioxidant capacity. In addition, CLP caused increased expression of the inflammatory markers tumor necrosis factor alpha, interleukin 1beta protein levels, and nuclear factor kappa B immunoexpression. Finally, CLP operated rats exhibited an upregulation in the apoptotic mediators, caspase 3, and P-C-Jun N-terminal kinases (JNK) proteins. FEB treatment of CLP rats caused a significant improvement and normalization in all measured parameters. Moreover, FEB amerliorates degenerative histopathological changes and improves the overall survival rate. In conclusion, FEB exhibited a protective effect in sepsis-induced liver and kidney injuries most probably through its anti-inflammatory, antioxidant, and antiapoptotic properties and attenuating JNK signaling pathway secondary to its XO enzyme inhibitory activity.