Urinary tract infections (UTIs) and interstitial cystitis (IC) are two pathologic conditions of the urinary system which predominately affect women and which have medical, psychological, sociological and economic implications. The unifying hypothesis of this proposal is that nitric oxide (NO), a small lipophilic gaseous molecule, which is released from non-adrenergic, non-cholinergic neurons and which is synthesized in a variety of mammalian tissues including macrophages and neutrophils, acts as a mediator in UTIs and IC. The applicants have: 1) shown that nitric oxide synthase (NOS) activity and cyclic GMP levels are elevated in the urine of patients with a UTI and decreased in the urine of patients with IC; 2) providing the first definitive molecular evidence for the presence of a biologically active inducible NOS (iNOS) in human neutrophils during an infectious process; and 3) shown that L-arginine administration to IC patients increases NOS activity and urinary cyclic GMP and Nox (nitrate plus nitrite) levels, and results in a decrease in IC related symptoms. To test their hypothesis they plan to: 1) determine factors, including cytokines and bacterial products, that mediate the production of nitric oxide in isolated human neutrophils, and to determine if and how neutrophil produced NO is involved in phagocytosis and bacterial killing; 2) identify the inflammatory agents, i.e., bacterial products and cytokines, enzymatic reactions, and cell types, that are involved in the induction of NOS during the initiation of and reparative response to inflammatory/infectious processes in the urinary tract; 3) characterize the subcellular localization and the post translational modifications that regulate human iNOS (hiNOS) expression using an in vitro heterologous system; and 4) determine the relationship between inflammatory cell identity, nitric oxide, prostaglandin and cytokine production, and IC related symptoms. The interpretation of the data obtained will not only pertain to infectious/inflammatory processes of he urinary tract, but also will facilitate the understanding of processes in humans which are less amenable to investigation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Special Emphasis Panel (ZRG4-UROL (01))
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Nyberg, Leroy M
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Yale University
Schools of Medicine
New Haven
United States
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Wheeler, Marcia A; Ayyagari, Rajasekhara R; Wheeler, George L et al. (2005) Regulation of cyclic nucleotides in the urinary tract. J Smooth Muscle Res 41:1-21
Salz, Whitney; Eisenberg, Dan; Plescia, Janet et al. (2005) A survivin gene signature predicts aggressive tumor behavior. Cancer Res 65:3531-4
Kang, Walter S; Tamarkin, Frank J; Wheeler, Marcia A et al. (2004) Rapid up-regulation of endothelial nitric-oxide synthase in a mouse model of Escherichia coli lipopolysaccharide-induced bladder inflammation. J Pharmacol Exp Ther 310:452-8
Sheryka, Elinore; Wheeler, Marcia A; Hausladen, Derek A et al. (2003) Urinary interleukin-8 levels are elevated in subjects with transitional cell carcinoma. Urology 62:162-6
Hausladen, Derek A; Wheeler, Marcia A; Altieri, Dario C et al. (2003) Effect of intravesical treatment of transitional cell carcinoma with bacillus Calmette-Guerin and mitomycin C on urinary survivin levels and outcome. J Urol 170:230-4
Smith, S D; Wheeler, M A; Plescia, J et al. (2001) Urine detection of survivin and diagnosis of bladder cancer. JAMA 285:324-8
Wheeler, M A; Yoon, J H; Olsson, L E et al. (2001) Cyclooxygenase-2 protein and prostaglandin E(2) production are up-regulated in a rat bladder inflammation model. Eur J Pharmacol 417:239-48
Korting, G E; Smith, S D; Wheeler, M A et al. (1999) A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol 161:558-65
Swana, H S; Smith, S D; Perrotta, P L et al. (1999) Inducible nitric oxide synthase with transitional cell carcinoma of the bladder. J Urol 161:630-4
Smith, S D; Wheeler, M A; Weiss, R M (1998) Detection of urinary tract infections by reduction of nitroblue tetrazolium. Kidney Int 54:1331-6

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