Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis
Bacterial infection-mediated mucosal signalling induces local renal ischaemia as a defence against sepsis
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DOI：
10.1111/j.1462-5822.2008.01182.x
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发表时间：
2008-10-01
影响因子：
3.4
通讯作者：
Richter-Dahlfors, Agneta
中科院分区：
文献类型：
--
作者：
Melican, Keira;Boekel, Jorrit;Richter-Dahlfors, Agneta
上行性尿路感染会对肾脏结构和功能造成广泛损害。我们使用了许多先进的技术，包括多光子显微镜，在活体动物体内研究了泌尿系致病性大肠埃希氏菌引起的肾盂肾炎的关键早期阶段。我们的结果揭示了一种以前未描述的对粘膜感染的先天血管反应，允许分离和根除病原体。宿主对粘膜感染的反应非常迅速，在3-4小时内触发了一系列事件。上皮信号导致细胞O(2)消耗增加，并通过凝血影响微血管流动，导致局限性缺血。随后的缺血损伤影响了病理生理学，肌动蛋白重排和上皮细胞塌陷导致细胞旁细菌运动。裸露的管状基底膜可以阻止细菌的立即传播，让宿主有时间通过凝血来隔离感染。肝素治疗抑制凝血导致致命的尿毒症。在临床上，这些发现可能与肾盂肾炎患者使用抗生素有关，也可能与败血症患者使用抗凝剂有关。
Ascending urinary tract infections can cause extensive damage to kidney structure and function. We have used a number of advanced techniques including multiphoton microscopy to investigate the crucial early phases of uropathogenic Escherichia coli induced pyelonephritis within a living animal. Our results reveal a previously undescribed innate vascular response to mucosal infection, allowing isolation and eradication of the pathogen. The extremely rapid host response to mucosal infection was highlighted by the triggering of a cascade of events within 3-4 h. Epithelial signalling produced an increase in cellular O(2) consumption and affected microvascular flow by clotting, causing localized ischaemia. Subsequent ischaemic damage affected pathophysiology with actin re-arrangement and epithelial sloughing leading to paracellular bacterial movement. A denuded tubular basement membrane is shown to hinder immediate dissemination of bacteria, giving the host time to isolate the infection by clotting. Suppression of clotting by heparin treatment caused fatal urosepsis. Clinically these findings may be relevant in antibiotics delivery in pyelonephritis patients and to the use of anticoagulants in sepsis.