Glucocorticoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock.
In the present study, we used glucocorticoid-induced tumor necrosis factor (TNF) receptor family gene knockout (GITR-KO) mice to evaluate a possible role of GITR on the pathogenesis of splanchnic artery occlusion (SAO) shock, which was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were killed for histological examination and biochemical studies. There was a marked increase in the lipid peroxidation in the ileum of the SAO-shocked, GITR wild-type (WT) mice after reperfusion. The absence of GITR significantly reduced the lipid peroxidation in the intestine. SAO-shocked WT mice developed a significant increase of ileum tissue, TNF-alpha, and myeloperoxidase activity and marked histological injury. SAO shock was also associated with a significant mortality (5% survival at 24 h after reperfusion). Reperfused ileum tissue sections from SAO-shocked WT mice showed positive staining for P-selectin, intercellular adhesion molecule 1 (ICAM-1), and E-selectin. The intensity and degree of P-selectin, E-selectin, and ICAM-1 were markedly reduced in tissue section from SAO-shocked, GITR-KO mice. SAO-shocked, GITR-KO mice also showed a significant reduction of the TNF-alpha production and neutrophil infiltration into the reperfused intestine, an improved histological status of the reperfused tissues, and an improved survival. Taken together, our results clearly demonstrate that GITR plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of GITR expression may represent a novel and possible strategy.
Cuzzocrea
Salvatore
S
Dipartimento Clinico, Sperimentale di Medicina, Farmacologia, Torre Biologica, Policlinico Universitario, Messina, Messina, Italy. salvator@unime.it
Nocentini
Giuseppe
G
Di Paola
Rosanna
R
Mazzon
Emanuela
E
Ronchetti
Simona
S
Genovese
Tiziana
T
Muià
Carmelo
C
Caputi
Achille P
AP
Riccardi
Carlo
C
D000818:Animals; D002445:Celiac Artery / Q000503:physiopathology / Q000601:surgery; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007082:Ileum / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D017538:Mesenteric Artery, Superior / Q000503:physiopathology / Q000601:surgery; D008641:Mesenteric Vascular Occlusion / Q000150:complications / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D015427:Reperfusion Injury / Q000235:genetics*; D012769:Shock / Q000209:etiology / Q000235:genetics*; D013152:Splanchnic Circulation / Q000502:physiology*; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D019040:E-Selectin; D053450:Glucocorticoid-Induced TNFR-Related Protein; D019007:P-Selectin; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase