Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection
Endogenous tissue-type plasminogen activator is protective during ascending urinary tract infection
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DOI：
10.1093/ndt/gfn562
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发表时间：
2009-03-01
影响因子：
6.1
通讯作者：
Florquin, Sandrine
中科院分区：
文献类型：
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作者：
Roelofs, Joris J. T. H.;Rouschop, Kasper M. A.;Florquin, Sandrine
背景急性肾盂肾炎是最常见的细菌感染之一。组织型纤溶酶原激活剂（tPA）是一种有效的纤溶剂，但也可在炎症过程中发挥作用。我们通过膀胱内接种10（10）CFU尿路致病性大肠杆菌1677诱导tPA（-/-）和C57 BL/6野生型（WT）小鼠肾盂肾炎。在24和48小时后处死小鼠，之后测定肾匀浆中的细菌生长和细胞因子水平。通过髓过氧化物酶-ELISA定量中性粒细胞的流入。测定中性粒细胞吞噬功能和氧化爆发。tPA（-/-）肾脏含有显著更高数量的E。大肠杆菌CFU，伴随着更高水平的白细胞介素-1 β（IL-1 β）和肿瘤坏死因子-α（TNF-α）。在两个时间点，tPA（-/-）和WT小鼠中浸润的中性粒细胞数量相似，表明tPA（-/-）中性粒细胞清除E.杆菌E.大肠杆菌在tPA（-/-）中性粒细胞中没有减少。有趣的是，tPA（-/-）中性粒细胞在E.大肠埃希菌比野生型中性粒细胞。与重组tPA孵育可完全逆转这种效应。这些结果表明，小鼠中tPA基因的缺失导致tPA（-/-）中性粒细胞的杀菌潜力降低，这导致实验性肾盂肾炎期间细菌生长显著增加。
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-1 beta (IL-1 beta) 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.