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

In the present study, we used TNF‐α receptor 1 knockout (TNF‐αR1KO) mice to evaluate a possible role of TNF‐α 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 cel...

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Bibliographic Details
Published in:Journal of leukocyte biology 2007-04, Vol.81 (4), p.1032-1043
Main Authors: Esposito, Emanuela, Mazzon, Emanuela, Muià, Carmelo, Meli, Rosaria, Sessa, Edoardo, Cuzzocrea, Salvatore
Format: Article
Language:English
Subjects:
adhesion molecules
Animals
Apoptosis
bcl-2-Associated X Protein - metabolism
Cell Adhesion Molecules - metabolism
Etanercept
Fas Ligand Protein - metabolism
Immunoglobulin G - pharmacology
Immunohistochemistry
Immunosuppressive Agents - pharmacology
Intestines - cytology
Intestines - physiology
Ischemia - genetics
Ischemia - mortality
Ischemia - therapy
Lipid Peroxidation
Male
Mice
Mice, Knockout
Neutrophil Infiltration
Proto-Oncogene Proteins c-bcl-2 - metabolism
Receptors, Tumor Necrosis Factor
Recombinant Fusion Proteins - pharmacology
Reperfusion Injury - genetics
Reperfusion Injury - mortality
Reperfusion Injury - therapy
Splanchnic Circulation
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
Tumor Necrosis Factor-alpha - physiology
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Summary:In the present study, we used TNF‐α receptor 1 knockout (TNF‐αR1KO) mice to evaluate a possible role of TNF‐α 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‐α 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‐αR1KO mice. Ischemia and reperfusion‐injured TNF‐αR1KO 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‐α 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‐α plays an important role in the ischemia and reperfusion injury and put forward the hypothesis that modulation of TNF‐α expression may represent a novel and possible strategy.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.0706480