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首页> 外文学位 >Mechanisms of bladder barrier dysfunction during neurogenic cystitis: The role of TNF and mast cells.
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Mechanisms of bladder barrier dysfunction during neurogenic cystitis: The role of TNF and mast cells.

机译：神经性膀胱炎期间膀胱屏障功能障碍的机制：TNF和肥大细胞的作用。

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摘要

The primary function of the human urinary bladder is to store urine, while maintaining a permeability barrier that protects underlying tissues from noxious urinary components. Inflammatory diseases of the bladder, including urinary tract infection (UTI) and interstitial cystitis (IC), afflict millions of patients in the US annually and cause significant patient morbidity due to pelvic pain, urinary frequency, and urgency. The symptoms associated with IC are thought to result from the loss of permeability barrier function. While it is understood that in UTIs, bacteria can mediate barrier dysfunction via apoptotic mechanisms, the pathogenesis of barrier dysfunction in IC is unknown. Understanding the mechanism of barrier dysfunction in IC may identify novel diagnostics targets and therapies.; We have characterized a mouse model of pseudorabies virus (PRV)-induced neurogenic cystitis, which will allow us to use genetic approaches in dissecting out the mechanisms of barrier dysfunction. Neurogenic cystitis is associated with the differential trafficking and activation of distinct mast cell pools in the bladder. Furthermore, neurogenic cystitis resulted in a decrease in trans-epithelial resistance (TER), an indication of barrier dysfunction, due to focal apoptosis of superficial urothelial cells, and this TNF-dependent event was mediated primarily by TNF receptor 1. The apoptotic process required mast cells and was preceded by migration of bladder mast cells toward the urothelium. Finally, we sought to identify chemokines, which promote bladder mast cell migration, and can be used as therapeutic targets for stabilizing barrier function in neurogenic cystitis. PRV-infection induces RANTES expression in the urothelium of mice and temporally coincident with lamina propria mast cell accumulation. Administration of neutralizing RANTES antibody abrogated lamina mast cell accumulation reduced the prevalence of urothelial lesion formation, and stabilized bladder TER in PRV-infected mice. These data suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.
机译：人膀​​胱的主要功能是存储尿液，同时保持渗透性屏障，保护下面的组织免受有害的尿液成分的侵害。膀胱炎性疾病，包括尿路感染（UTI）和间质性膀胱炎（IC），在美国每年折磨数百万患者，并由于骨盆疼痛，尿频和尿急引起严重的患者发病率。据认为，与IC相关的症状是由渗透屏障功能的丧失引起的。尽管已经知道在UTI中，细菌可以通过凋亡机制介导屏障功能障碍，但是IC中屏障功能障碍的发病机理尚不清楚。了解IC中屏障功能障碍的机制可能会确定新的诊断目标和疗法。我们已经表征了伪狂犬病病毒（PRV）诱导的神经源性膀胱炎的小鼠模型，这将使​​我们能够使用遗传方法剖析屏障功能障碍的机制。神经源性膀胱炎与膀胱中不同的肥大细胞池的差异运输和激活有关。此外，由于浅层上皮细胞的局部凋亡，神经源性膀胱炎导致跨上皮抵抗（TER）的降低，这是屏障功能障碍的迹象，并且这种依赖TNF的事件主要由TNF受体1介导。肥大细胞，然后是膀胱肥大细胞向尿路上皮迁移。最后，我们寻求鉴定促进膀胱肥大细胞迁移的趋化因子，并可用作稳定神经源性膀胱炎中屏障功能的治疗靶标。 PRV感染诱导小鼠尿路上皮中的RANTES表达，并在时间上与固有层肥大细胞积聚相吻合。给予中和性RANTES抗体可消除层状肥大细胞积聚，从而降低尿路上皮病变形成的发生率，并稳定PRV感染小鼠的膀胱TER。这些数据表明趋化因子可能代表患有肥大细胞相关疾病的IC患者的新型治疗靶点。

著录项

  • 作者

    Chen, Michael C.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Health Sciences Pathology.; Biology Physiology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 237 p.
  • 总页数 237
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 病理学;
  • 关键词

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