Objectives: Hepatic ischemia and reperfusion during liver transplant surgery result in hepatocellular damage. Toll-like receptors, especially TLR4, have a fundamental basic role in the inflammatory phase of ischemia-reperfusion injuries. The effect of the TRIF-dependent signaling pathway downstream of TLR4 in hepatic ischemia-reperfusion injury has been well established. However, the role of TLR4-MyD88-dependent signal transduction in hepatic ischemia-reperfusion injury has not yet been clarified. The interferon regulatory factor 5 was introduced as the main regulator of the TLR4-MyD88 signaling pathway for activating proinflammatory cytokines. The present study was carried out to investigate the functional impact of the TLR4/IRF5 signaling axis in hepatic ischemia-reperfusion injury.
Materials and methods: mRNA expression levels of TLR4, IRF5, tumor necrosis factor α, interleukin 1β, and interleukin 6 were measured using real-time polymerase chain reaction after short (3 h) and long (168 h) reperfusion periods in a hepatic mouse model of ischemia-reperfusion injury in the presence and absence of N-acetylcysteine. Liver damage was evaluated by plasma levels of alanine aminotrans-ferase and histopathology.
Results: Our results show that mRNA levels of TLR4/IRF5 and its downstream cytokines were significantly elevated 3 hours after reperfusion and had drastically fallen to baseline levels 168 hours after reperfusion. Plasma levels of alanine aminotransferase showed the same pattern. Histopathologic study of the samples revealed significant hepatic cell infiltration and necrosis 168 hours after reperfusion. Pretreatment with N-acetylcysteine significantly decreased the mRNA levels of TLR4/IRF5 and its downstream cytokines 3 hours after reperfusion and subsequently improved the previously mentioned hepatic damages 168 hours after reperfusion.
Conclusions: This study suggests a possible role for the TLR4/IRF5 signaling pathway in hepatic ischemia-reperfusion injury. Furthermore, it reveals that N-acetylcysteine may suppress this inflammatory axis and consequently improve hepatic injuries.