Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection.
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 10(10) 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-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha). 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.
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. j.j.roelofs@amc.uva.nl
Joris J T H
JJ
Roelofs
Kasper M A
KM
Rouschop
Gwendoline J D
GJ
Teske
Gerry T M
GT
Wagenaar
Nike
N
Claessen
Jan J
JJ
Weening
Tom
T
van der Poll
Sandrine
S
Florquin
D000818:Animals; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology; D010587:Phagocytosis; D011704:Pyelonephritis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D016897:Respiratory Burst / Q000502:physiology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator