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

Abstract

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-κB and AP-1 participated in the cascade of events leading to TNF-α production, neutrophil recruitment, tissue injury and lethality following intestinal I/R. The superior mesenteric artery (SMA) of mice was made ischaemic for 60 min followed by 30 min of reperfusion. The effects of NF-κB 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-α]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-α]pyridazine-5-carboxamide). After I/R, there was increase of translocation of NF-κB but not of AP-1, in the intestine and lungs, as assessed by a gel shift assay. 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-α production, but did not alter neutrophil recruitment. Treatment with MOL-294 inhibited reperfusion-associated lethality, an effect likely to be secondary to the inhibition of systemic TNF-α levels. PNRI-299 had no effects on the inflammatory changes or lethality induced by I/R injury. Our results point to an important role for NF-κB in triggering endogenous proinflammatory networks during intestinal I/R injury. Inhibition of NF-κB prevents tissue injury and lethality, and this was associated with inhibition of TNF-α production and decrease in neutrophil recruitment. © 2005 Nature Publishing Group. All rights reserved.