Nuclear factor kB inactivation in the rat liver ameliorates short term total warm ischaemia/reperfusion injury

Background: In hepatic ischaemia/reperfusion injury, activated liver macrophages (Kupffer cells) are dominantly regulated by a transcription factor, nuclear factor k B (NF k B), with respect to expression of inflammatory cytokines, acute phase response proteins, and cell adhesion molecules. Aims: We assessed whether inactivation of NF k B in the liver could attenuate total hepatic warm ischaemia/reperfusion injury. Methods: We studied rats with hepatic overexpression of inhibitor k B a super-repressor (I k B a SR) caused by a transgene introduced using an adenoviral vector. Hepatic ischaemia/reperfusion injury was induced under warm conditions by total occlusion of hepatoduodenal ligament structures for 20 minutes, followed by reperfusion. Controls included uninfected and control virus (AdLacZ) infected rats. Results: I k B a SR was overexpressed in Kupffer cells as well as in hepatocytes, blocking nuclear translocation of NF k B (p65) into the nucleus after reperfusion. Gene transfection with I k B a SR, but not with LacZ, markedly attenuated ischaemia/reperfusion injury, suppressing inducible nitric oxide synthase and nitrotyrosine expression in the liver. Moreover, no remarkable hepatocyte apoptosis was detected under I k B a SR overexpression. Conclusions: Adenoviral transfer of the I k B a SR gene in the liver ameliorates short term warm ischaemia/ reperfusion injury, possibly through attenuation of hepatic macrophage activation.

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