Tumor necrosis factor promotes differential trafficking of bladder mast cells in neurogenic cystitis

Purpose: IC is often considered neurogenic cystitis, in which mast cells are involved in a positive feedback loop that results in sustained urothelial inflammation. To characterize these processes we developed a murine model of neurogenic cystitis using Bartha's strain of PRV based on a similar model in the rat. Materials and Methods: Female C57BL/6 mice (National Cancer Institute, Bethesda, Maryland) were used in the study. Neurogenic cystitis was induced by the injection of Bartha's strain of PRV (2.2 × 10⁶ pfu) into the abductor caudalis dorsalis tail base muscle. Bladder inflammation was assessed by leukocyte influx and Evans blue dye extravasation. Mast cells were visualized in bladder tissue by staining with 0.1% toluidine blue. Results: Inoculation with PRV in the abductor caudalis dorsalis resulted in cystitis within 3 days. Coincident with the induction of cystitis mast cells accumulated in the lamina propria due to mast cell trafficking from the proximal detrusor (relative to the lumen), whereas mast cells from the distal detrusor were unchanged and total mast cell counts were not increased. Degranulated mast cells increased approximately 20-fold in the lamina propria of infected mice relative to controls. In TNF receptor 1/2 deficient mice (Jackson Laboratory, Bar Harbor, Maine) mast cell trafficking was not observed in response to PRV and mast cells were not degranulated. Conclusions: These data indicate that neurogenic cystitis is associated with the differential trafficking and activation of distinct mast cell pools in the bladder. Since TNF mediates these events, anti-TNF therapy may mitigate the pathogenesis of neurogenic cystitis.