ISCHEMIA-REPERFUSION ACTIVATES THE NUCLEAR TRANSCRIPTION FACTOR NF-KAPPA-B AND UP-REGULATES MESSENGER-RNA SYNTHESIS OF ADHESION MOLECULES IN THE LIVER IN-VIVO

Hepatic ischemia-reperfusion induces a neutrophil-induced injury, whic h is dependent on adhesion molecules. The transcription factor NF-kapp a B plays a key role in the activation of adhesion molecule gene expre ssion in vitro. To investigate activation of NF-kappa B and initiation of adhesion molecule gene transcription in the liver in vivo Fischer rats were subjected to 30 min of hepatic ischemia and up to 24 h of re perfusion. A moderate baseline activation of NF-kappa B was found in t he liver in sham-operated controls and during ischemia, however, at 1 h and 5 h reperfusion, nuclear NF-kappa B DNA-binding activity increas ed by 270-300% as determined by densitometric analysis of electrophore tic mobility shift assays, At 24 h, NF-kappa B was still activated by 140% above sham control levels. NF-kappa B complexes consisted of subu nits p50 and p65 (RelA). In addition, nuclear translocation of the tra nscription factor C/EBP beta was increased during reperfusion. Norther n blot analysis of RNA isolated from the intact liver showed minor int ercellular adhesion molecule-1(ICAM-1) mRNA expression in sham control s, a moderate but significant increase during ischemia and a further s ignificant increase during reperfusion. Isolation of hepatic endotheli al cells demonstrated transiently increased gene transcription for ICA M-1, vascular adhesion molecule-1 (VCAM-1), E-and P-selectin at 1 h re perfusion. In the nonischemic lobes a similar time course of NF-kappa B activation and ICAM-1 mRNA formation was observed during reperfusion suggesting the involvement of circulating mediators. The data support the conclusion that hepatic ischemia-reperfusion induces NF-kappa B a nd C/EBP beta activation and enhances transcription of cellular adhesi on molecule genes in the liver. (C) 1997 Elsevier Science Ireland Ltd.