NDT Advance Access published online on October 8, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn562
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Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection
1 Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam 2 Department of Pediatrics, Leiden University Medical Center, Leiden 3 Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Correspondence and offprint requests to: Joris J. T. H. Roelofs, Department of Pathology, Room H2-131, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel: +31-20-5669111; Fax: +31-20-5669523; E-mail: j.j.roelofs{at}amc.uva.nl
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Abstract |
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Background. Acute pyelonephritis is one of the most common bacterial infections. Tissue-type plasminogen activator (tPA) is a potent fibrinolytic agent, but can play a role in inflammatory processes as well.
Methods. We induced pyelonephritis in tPA–/– and C57BL/6 wild-type (WT) mice by intravesical inoculation with 1010 CFU uropathogenic Escherichia coli 1677. The mice were killed after 24 and 48 h, after which bacterial outgrowth and cytokine levels in kidney homogenates were determined. Influx of neutrophils was quantified by myeloperoxidase-ELISA. Neutrophil phagocytosis and oxidative burst were measured.
Results. The tPA–/– kidneys contained significantly higher numbers of E. coli CFU, accompanied by higher levels of interleukin-1β (IL-1β) and tumour necrosis factor-
(TNF-). The number of infiltrating neutrophils was similar in tPA–/– and WT mice at both time points, suggesting that tPA–/– neutrophils have a lower ability to eliminate E. coli. Phagocytosis of E. coli organisms was not diminished in tPA–/– neutrophils. Interestingly, tPA–/– neutrophils showed a significantly lower ability to generate an oxidative burst reaction upon stimulation with E. coli than WT neutrophils. Incubation with recombinant tPA reversed this effect completely.
Conclusions. These results show that deletion of the tPA-gene in mice leads to lower bactericidal potential of tPA–/– neutrophils, which results in significantly more bacterial outgrowth during experimental pyelonephritis.
Keywords: fibrinolytic system; neutrophil; pyelonephritis; oxidative burst; tissue-type plasminogen activator
4 Present address: Department of Radiation Oncology, Research Institute Growth and Development, University of Maastricht, Maastricht, The Netherlands.
Received for publication: 28.10.07
Accepted in revised form: 15. 9.08