NF‐ κ B 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‐ κ B and AP‐1 participated in the cascade of events leading to TNF‐ α 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‐ κ B 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‐ κ B, 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‐ α 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‐ α 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‐ κ B in triggering endogenous proinflammatory networks during intestinal I/R injury. Inhibition of NF‐ κ B prevents tissue injury and lethality, and this was associated with inhibition of TNF‐ α production and decrease in neutrophil recruitment.British Journal of Pharmacology (2005) 145 , 246–254. doi: 10.1038/sj.bjp.0706190