Redox-sensitive transcription factors NF-κB and AP-1 are involved in the hepatic protection from ischemia-reperfusion injury (IRPI) by the atrial natriuretic peptide (ANP)

Abstract

Background: Ischemia-reperfusioninjury (IRPI) is a major clinical problem after liver transplantation. We have shown that ANP prevents IRPI of the rat liver after 24 h storage in cold UW solution. ANP seems to interfere with oxidative stress during IRPI, the mechanisms remain to be detined. Therefore, aim of this study was to investigate potential mechanisms of ANP protection, particularly effects on redox-sensitive transcription factors. Methods: Livers of male Sprague-Dawley rats were perfused in a nonrecirculating fashion with or without ANP (200 nM, n=4 each)for 20 min preceeding24 h storage in UW solution. Adenosine nucleotide concentration, activation of NP-KB and AP-1 (EMSA), as well as mRNA coding for iNOS, COX-2 andTNP-a mRNA (Northern Blot) were determinedin heeze clamped liver samples during 2 h of reperfusion. Results: ANP prevented IRPI as shown by significant improvement of bile flow, reduction of sinusoidal release of LDH andPNP and histological analysis. ANP had no effect on portal pressure increase as indicator of impaired hepatic circulation, nor on energy depletion determined by adenosine nucleotide decrease. During reperfusion NF-KB (at 45 min) and AP-1 (120 min) binding activities were severalfold augmented accompanied by increased TNP-a mRNA expression. ANP pretreatment clearly reduced these effects. Since neither iNOS nor COX-2 mRNA could be detectedduring 2 h mperfusion, an involvement of these two inflammatory enzymes in our model of IRPI is unlikely. Conclusions: Hepaticprotection from coldIRP1 by ANP is not linked to vasodilation nor to an influence on intracellular energy status. Suppression of NF-KB and AP-1 activation by ANP seems to be involved. INTRA-GRAFT PROLIFJlRATION OF NAIVE AND MEMORY T LYMPHOCYTES DURING HEPATIC ALLOGRAFT REJECTION MM Dollinaer’~*. SEM Howie’, JN Plev&. PC Haves* DJ