Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion
Donnahoo, K.K.; Meng, X.; Ayala, A.; Cain, M.P.; Harken, A.H.; Meldrum, D.R.
American Journal of Physiology 277(3): R922-R929
1999
ISSN/ISBN: 0002-9513 PMID: 10484513 Document Number: 501196
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.