While the etiology of Interstitial Cystitis (IC) is unknown, prior investigations indicate the existence of an inflammatory condition as evidenced by the presence of mast cells and other inflammatory cells in abnormally high numbers in the submucosal and detrusor layers of the bladder epithelium. Such inflammation, which may be initiated by any number of immunologic stimuli, could be maintained and/or augmented by neurogenic impulses. Neurotransmitters such as substance P (SP) and neurotensin (NT), released from sensory nerves and associated interneurons in the bladder can promote plasma extravasation (via mast cell histamine) and immune cell chemotaxis (via leukotrienes), infiltration of the tissue space by immune cells and a proliferation of resident lymphocytes, macrophages and mast cells. These inflammatory cells, in the presence of SP and/or NT display enhanced phagocytosis and release granular enzymes. We have shown that these proteases can act on plasma proteins to generate far larger amounts of NT-related peptides (e.g., histamine related peptide, HRP) which can feed back to further stimulate mast cell histamine and leukotriene output. Thus, we hypothesize that neurogenic stimuli such as SP and NT may lead to an inflammatory spiral which progresses out of control by way of positive feedback reinforcement, and can therefore progress to a chronic state such as is characteristic of IC. To this end five specific aims will be addressed. 1. To determine whether SP, NT, and HRP play role(s) in exacerbating and/or maintaining chronic inflammation in animal models of cystitis. 2. To compare inflamed and normal rat bladders with regard to SP, NT and HRP receptor number and localization. 3. To examine responses of cultured cells to SP, NT, and HRP with regard to cytokine, prostaglandin and leukotriene generation. 4. To compare inflamed bladder from IC patients with controls with regard to SP, NT, and HRP receptor number and localization as well as cytokine production. 5. To measure SP, NT and HRP as well as histamine leukotriene, and TNFalpha in the urine of IC patients and controls.
| Mitra, S; Dagher, A; Kage, R et al. (1999) Experimental autoimmune cystitis: further characterization and serum autoantibodies. Urol Res 27:351-6 |
| Luber-Narod, J; Austin-Ritchie, T; Banner, B et al. (1996) Experimental autoimmune cystitis in the Lewis rat: a potential animal model for interstitial cystitis. Urol Res 24:367-73 |
