Activation of Endogenous Anti-Inflammatory Mediator Cyclic AMP Attenuates Acute Pyelonephritis in Mice Induced by Uropathogenic Escherichia coli
Activation of Endogenous Anti-Inflammatory Mediator Cyclic AMP Attenuates Acute Pyelonephritis in Mice Induced by Uropathogenic Escherichia coli
复制标题
内源性抗炎介质环 AMP 的激活可减轻尿路病原性大肠杆菌引起的小鼠急性肾盂肾炎
DOI：
10.1016/j.ajpath.2014.10.007
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发表时间：
2015-02-01
影响因子：
6
通讯作者：
Zhou, Wuding
中科院分区：
文献类型：
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作者：
Wei, Yang;Li, Ke;Zhou, Wuding
由尿路致病性大肠杆菌（UPEC）引起的肾盂肾炎的发病机制尚不清楚。在这里，我们发现除了 UPEC 毒力外，宿主先天免疫反应的严重程度和肾上皮细胞的侵袭也是重要的致病因素。内源性抗炎介质 cAMP 的激活可显着减轻 UPEC 诱导的小鼠急性肾盂肾炎。给予毛喉素（一种有效的细胞内 cAMP 提升剂）可减少肾脏感染（即细菌负荷、组织破坏）；这与局部炎症减弱有关，肾脏产生的促炎介质、炎症细胞的肾浸润和肾髓过氧化物酶活性的减少就证明了这一点。在原代细胞培养系统中，毛喉素不仅下调肾小管上皮细胞和炎症细胞（例如单核细胞/巨噬细胞）产生的 UPEC 刺激的促炎介质，而且还减少肾小管上皮细胞的细菌内化。我们的研究结果清楚地表明，内源性抗炎介质 cAMP 的激活有利于控制 UPEC 介导的小鼠急性肾盂肾炎。这种有益效果至少可以部分地通过作用于肾小管上皮细胞和炎症细胞以及通过抑制细菌侵入肾小管上皮细胞来限制过度炎症反应来解释。
The pathogenesis of pyelonephritis caused by uropathogenic Escherichia coli (UPEC) is not well understood. Here, we show that besides UPEC virulence, the severity of the host innate immune response and invasion of renal epithelial cells are important pathogenic factors. Activation of endogenous anti-inflammatory mediator cAMP significantly attenuated acute pyelonephritis in mice induced by UPEC. Administration of forskolin (a potent elevator of intracellular cAMP) reduced kidney infection (ie, bacterial load, tissue destruction); this was associated with attenuated Local inflammation, as evidenced by the reduction of renal production of proinflammatory mediators, renal infiltration of inflammatory cells, and renal myeloperoxidase activity. In primary cell culture systems, forskolin not only down-regulated UPEC-stimulated production of proinflammatory mediators by renal tubular epithelial cells and inflammatory cells (eg, monocyte/macrophages) but also reduced bacterial internalization by renal tubular epithelial cells. Our findings clearly indicate that activation of endogenous anti-inflammatory mediator cAMP is beneficial for controlling UPEC-mediated acute pyelonephritis in mice. The beneficial effect can be explained at least in part by Limiting excessive inflammatory responses through acting on both renal tubular epithelial cells and inflammatory cells and by inhibiting bacteria invasion of renal tubular epithelial cells.