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Published online before print January 8, 2007

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(Journal of Leukocyte Biology. 2007;81:1032-1043.)
© 2007 by Society for Leukocyte Biology

Splanchnic ischemia and reperfusion injury is reduced by genetic or pharmacological inhibition of TNF-

Emanuela Esposito^*,,1, Emanuela Mazzon^,,1, Carmelo Muià, Rosaria Meli^*, Edoardo Sessa and Salvatore Cuzzocrea^,,2

^* Department of Experimental Pharmacology, University of Naples "Federico II," Naples, Italy;
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy; and
IRCCS Centro Neurolesi "Bonino-Pulejo," Messina, Italy

² Correspondence: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina, Italy. E-mail: salvator{at}unime.it

In the present study, we used TNF- receptor 1 knockout (TNF-R1KO) mice to evaluate a possible role of TNF- on the pathogenesis of ischemia and reperfusion injury of the multivisceral organs. Ischemia and reperfusion injury was induced in mice by clamping the superior mesenteric artery and the celiac artery for 30 min, followed thereafter by reperfusion. Sixty minutes after reperfusion, animals were killed for histological examination and biochemical studies. Injured wild-type (WT) mice developed a significant increase of ileum TNF- levels, myeloperoxidase activity, and marked histological injury and apoptosis. Ischemia and reperfusion injury of the multivisceral organs was also associated with a significant mortality. Reperfused ileum sections from injured WT mice showed positive staining for P-selectin, VCAM, ICAM-1, and E-selectin. The intensity and degree of P-selectin, E-selectin, VCAM, and ICAM-1 were reduced markedly in tissue sections from injured TNF-R1KO mice. Ischemia and reperfusion-injured TNF-R1KO mice also showed a significant reduction of neutrophil infiltration into the intestine, a reduction of apoptosis, an improved histological status of the intestine, and survival. In addition, we investigated the effect of Etanercept, a TNF- soluble receptor construct, on ischemia and reperfusion injury of the multivisceral organs. Etanercept (5 mg/kg administered i.p. 5 min prior to reperfusion) significantly reduced the inflammatory response and the ileum injury. Taken together, our results clearly demonstrate that TNF- plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of TNF- expression may represent a novel and possible strategy.

Key Words: adhesion molecules • Etanercept • neutrophil infiltration

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