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.
Souza
Danielle G
DG
Immunopharmacology, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, 6627 Pampulha, 31270-901 Belo Horizonte MG, Brazil.
Vieira
Angélica T
AT
Pinho
Vanessa
V
Sousa
Lirlândia P
LP
Andrade
Anderson A
AA
Bonjardim
Cláudio A
CA
McMillan
Michael
M
Kahn
Michael
M
Teixeira
Mauro M
MM
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000150:complications; D005759:Gastroenteritis / Q000378:metabolism*; D007422:Intestines / Q000098:blood supply*; D007511:Ischemia / Q000209:etiology / Q000378:metabolism; D008297:Male; D017538:Mesenteric Artery, Superior; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D011724:Pyridazines / Q000494:pharmacology; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism*; D013879:Thioredoxins / Q000037:antagonists & inhibitors; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
C468870:MOL 294; D016328:NF-kappa B; C480123:PNRI299; D011724:Pyridazines; D018808:Transcription Factor AP-1; D014230:Triazoles; D013879:Thioredoxins