NF-kappaB plays a major role during the systemic and local acute inflammatory response following intestinal reperfusion injury.

1 The nuclear translocation of transcription factors may be a critical factor in the intracellular pathway involved in ischaemia/reperfusion (I/R) injury. Here, we examined whether NF-kappaB and AP-1 participated in the cascade of events leading to TNF-alpha production, neutrophil recruitment, tissue injury and lethality following intestinal I/R. 2 The superior mesenteric artery (SMA) of mice was made ischaemic for 60 min followed by 30 min of reperfusion. The effects of NF-kappaB and AP-1 were studied by the administration of the thioredoxin inhibitor, MOL-294 (methyl 4-hydroxy-4-(8-methyl-1,3-dioxo-2-phenyl-2,3,5,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazin-5-yl)but-2-ynoate), and the AP-1 inhibitor, PNRI-299 (N-benzyl-2-(3-cyanophenyl)-1,3,7-trioxo-2,3,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-5-carboxamide). After I/R, there was increase of translocation of NF-kappaB, but not of AP-1, in the intestine and lungs, as assessed by a gel shift assay. 3 Treatment with MOL-294 inhibited the increase in vascular permeability, neutrophil accumulation, hemorrhage and proinflammatory cytokine levels, induced by intestinal I/R injury in the intestine. In the lungs, MOL-294 partially inhibited edema formation, TNF-alpha production, but did not alter neutrophil recruitment. 4 Treatment with MOL-294 inhibited reperfusion-associated lethality, an effect likely to be secondary to the inhibition of systemic TNF-alpha levels. PNRI-299 had no effects on the inflammatory changes or lethality induced by I/R injury. 5 Our results point to an important role for NF-kappaB in triggering endogenous proinflammatory networks during intestinal I/R injury. Inhibition of NF-kappaB prevents tissue injury and lethality, and this was associated with inhibition of TNF-alpha production and decrease in neutrophil recruitment.