All-trans retinoic acid preconditioning protects against liver ischemia/reperfusion injury by inhibiting the nuclear factor kappa B signaling pathway

Background: Inflammatory response plays a pathogenic role in liver ischemia/reperfusion (I/R) injury. All-trans retinoic acid (ATRA) is an active metabolite of vitamin A with anti-inflammatory effects. However, there are few reports on the anti-inflammatory effects of ATRA on liver I/R injury. The purpose of this study was to investigate the effects of ATRA on liver I/R injury and related mechanisms. Methods: A total of 54 male Sprague-Dawley rats were randomly divided into three groups ( 18 rats each), namely, sham, I/R, and I/R + ATRA groups. ATRA was intraperitoneally administered at a dose of 15 mg/kg/d 14 d before ischemia surgery. The segmental (70%) hepatic ischemia model was used by clamping the portal vein, hepatic artery, and bile duct of the left and median for 1 h. The rats were sacrificed 3, 6, and 24 h after reperfusion, and blood and liver tissue samples were obtained. Liver injury was evaluated by biochemical and histopathologic examinations. Myeloperoxidase activity was spectrophotometrically measured. The expression of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Liver nuclear factor kappa B (NF-kappa B) was detected by immunohistochemistry. The expression of NF-kappa B p65 and inhibitor NF-kappa B-alpha (I kappa B alpha) was determined by Western blot analysis. Results: The serum alanine aminotransferase level, Suzuki scores of hepatic histology, and hepatic myeloperoxidase activity, as indices of hepatic injury, were increased after reperfusion. The increase was attenuated by preadministration with ATRA. Compared with the I/R group, ATRA treatment increased I kappa Ba expression and suppressed NF-kappa B p65 expression. Subsequently, the levels of tumor necrosis factor-alpha and interleukin-6 after liver I/R were effectively downregulated. Conclusions: ATRA administration can significantly attenuate I/R injury in rat liver. The protective mechanism is related to its anti-inflammatory function of inhibiting NF-kappa B activation. (c) 2013 Elsevier Inc. All rights reserved.