Glucocorficoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock

Salvatore Cuzzocrea, Giuseppe Nocentini, Rosanna Di Paola, Emanuela Mazzon, Simona Ronchetti, Tiziana Genovese, Carmelo Muià, Achille P. Caputi, Carlo Riccardi

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Abstract

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-α, 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-α 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.

Original languageEnglish
Pages (from-to)933-940
Number of pages8
JournalJournal of Leukocyte Biology
Volume76
Issue number5
DOIs
Publication statusPublished - Nov 2004

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Keywords

  • Adhesion molecules
  • Ischemia and reperfusion
  • Lipid peroxidation
  • Neutrophil infiltration

ASJC Scopus subject areas

  • Cell Biology

Cite this

Cuzzocrea, S., Nocentini, G., Di Paola, R., Mazzon, E., Ronchetti, S., Genovese, T., Muià, C., Caputi, A. P., & Riccardi, C. (2004). Glucocorficoid-induced TNF receptor family gene (GITR) knockout mice exhibit a resistance to splanchnic artery occlusion (SAO) shock. Journal of Leukocyte Biology, 76(5), 933-940. https://doi.org/10.1189/jlb.0204110