PROTECTIVE EFFECT OF WY14643 IN HEPATIC ISCHEMIA/REPERFUSION INJURY VIA SUPPRESSING THE ACTIVATION OF TLR4/NF-KB P65 SIGNAL PATHWAY.

Background: Hepatic ischemia/reperfusion (I/R) injury is a disaster common critical event which frequently occurs in a variety of clinical scenarios. To investigate the protective effect of Wy14643 (WY) precondition against hepatic ischemia/ reperfusion (I/R) injury in rats and its potential mechanism.
Methods: Thirty Sprague–Dawley male rats weighing 220-250 g were randomly divided into three groups (n=10) including the sham-operated +saline group (Sham), the ischemic-reperfusion+ vehicle (IRI), and the WY14643 preconditioning group (WY). The three groups were pretreated with saline, ethanol and WY, at 1 h before ischemia with a concentration of 10 mg/kg , respectively. Hepatic ischemia-reperfusion (I/R) was induced by clamping blood supply to the left lateral and median lobes of the liver for 90 min. Blood samples and liver tissues were obtained at the end of 4h reperfusion. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were measured. The histological changes of hepatic tissues were examanied by HE staining. The expression of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were detected by ELISA and RT-PCR. Moreover, the expression of TLR-4 , Iκβ-α, Myd88, p65 and PPAR- were detected by western blotting.
Result: After 4 h reperfusion, compared with the IRI group, the liver dysfunction (ALT, AST and LDH), damage score, the expression of TNF-α , IL-6, and IL-1β, the protein expression level of TLR4, Myd88, the phosphorylation level of Iκβ-α and p65 in the WY group was significantly decreased (all P<0.05); while the protein expression of Iκβ-α was increased (P<0.05) with no difference in the expression of p65 (P>0.05) .
Conclusion: Wy14643 precondition could protect liver againest I/R injury and the protective effect is associated with suppressing inflammation by reducing the activation of TLR-4/NF-κβ signaling.

Keywords
hepatic ischemia reperfusion injury; inflammation; Wy14643; TLR-4/NF-κB