Substance P induced release of macrophage migration inhibitory factor from rat bladder epithelium

Purpose: Substance P (SP), a neuropeptide mediator of neurogenic inflammation, induces vasodilatation, plasma extravasation and hypersensitivity in the bladder. SP induced inflammation is enhanced and maintained by the release of additional mediators. The rat urothelium contains pre-formed macrophage migration inhibitory factor (MIF), a known proinflammatory cytokine, suggesting that it may mediate bladder neurogenic inflammation. We documented the time course of SP effects on rat bladder inflammation. Materials and Methods: Subcutaneous SP administration induced neurogenic inflammation. The bladder, urine and serum were removed 15, 30, 60 and 120 minutes following treatment, and changes in MIF, nerve growth factor (NGF), c-fos and cox-2 were determined. Results: SP induced significant MIF and NGF release from the bladder following 30 minutes of exposure. cox-2 protein was detected at significant, levels following 60 minutes of SP exposure. Basal c-fos protein could be detected in control bladders with significant increases following 60 minutes of SP exposure. Histological examination of bladder tissue showed increased edema in SP treated bladders. Conclusions: SP stimulated early release of urothelial MIF as well as increased MIF gene expression in this model of neurogenic inflammation. SP also increased expression of the proinflammatory mediator NGF. In addition, increases in cox-2 enzyme and c-fos transcription factor were noted. The early release of MIF suggests that it is an immediate proinflammatory regulator in the bladder and it establishes MIF as candidate proinflammatory mediator of SP induced neurogenic inflammation. These data continue to support our hypothesis that MIF is a new target for intervention in bladder inflammation.