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Am J Physiol Regul Integr Comp Physiol 277: R922-R929, 1999;
0363-6119/99 $5.00
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Vol. 277, Issue 3, R922-R929, September 1999

RAPID COMMUNICATION
Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion

Kirstan K. Donnahoo1, Xianzhong Meng2, Alfred Ayala3, Mark P. Cain1, Alden H. Harken2, and Daniel R. Meldrum4

1 Department of Urology, Indiana University Medical Center, Indianapolis, Indiana 46202; 2 Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262; 3 Departments of Physiology and Immunology/Microbiology, Brown University School of Medicine, Providence, Rhode Island 02903; and 4 Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

The purpose of this study was to determine whether isolated renal ischemia and reperfusion (I/R) induces renal tumor necrosis factor (TNF) mRNA production, TNF protein expression, or TNF bioactivity and, if so, whether local/early TNF production acts as mediator of ischemia-induced, neutrophil-mediated renal injury. After rats were anesthetized, varying periods of renal ischemia, with or without reperfusion, were induced. Kidney mRNA content (RT-PCR), TNF protein expression (ELISA), TNF bioactivity (WEHI-164 cell clone cytotoxicity assay), and neutrophil infiltration [myeloperoxidase (MPO) assay] were determined. In other animals, renal MPO and serum creatinine were assessed after TNF was neutralized [binding protein (TNF-BP)]. Thirty minutes of ischemia induced renal TNF mRNA. TNF protein expression and bioactivity peaked after 1 h ischemia and 2 h reperfusion, whereas neutrophil infiltration peaked at 4 h reperfusion. TNF-BP neutralized TNF bioactivity, reduced neutrophil infiltration, and protected postischemic function. These results constitute the initial demonstration that 1) early renal tissue TNF expression contributes to neutrophil infiltration and injury after I/R and 2) TNF-BP may offer a new adjunctive therapy in renal preservation prior to planned ischemic insults.

tumor necrosis factor-binding protein; myeloperoxidase; polymorphonuclear leukocytes; neutrophils; cytokines; therapy


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