Mechanisms of Bladder Barrier Dysfunction during Neurogenic Cystitis: the Role of TNF and Mast Cells

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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.</

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  • 05/30/2018
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