Irradiation of the pelvic region can result in bladder inflammation and dysfunction. This cystitis or its likelihood also increases the incidence of bladder cancer, prohibits radiation treatment for bladder tumors, and limits the allowable radiation dose for treating other pelvic malignancies. The mechanism of radiation cystitis is unclear. It may involve activation of a mitochondria nitric oxide (NO) synthase (mtNOS) unique to the umbrella cells, disruption of the permeability barrier and infiltration of urine into the lamina propria. This in turn can lead to inflammation and increased collagen III deposition in the lamina propria. Decreased bladder compliance and dysfunction result. We have developed rodent models of radiation cystitis where irradiation results in decreased transepithelial resistance and increased urea and water permeabilities within 12 hours. At six months, cystometrograms show that bladder compliances and intercontractile intervals are decreased while residual volumes and baseline pressures are increased-features indicative of fibrosis. Prior transfection with the radioprotectant manganese superoxide dismutase (MnSOD) is only partially effective, most likely due to decreased peroxidase activity and excess hydrogen peroxide formation. However, novel intravesical therapy with a NOS inhibitor during irradiation, or irradiation of bladders devoid of mtNOS, offers almost complete protection. Inhibition of NO can prevent its reaction with superoxide (O2) to form peroxynitrite (ONO2-), which can damage complexes I and III of the respiratory chain and lead to apoptotic/necrotic cell death.
Specific Aim 1 will test the hypothesis that ionizing radiation activates mtNOS, resulting in reactive nitrogen and oxygen species (RNS and ROS) which disrupt the urothelial permeability barrier. We have developed NO and ONO2- microsensors which allow us to simultaneously measure in real-time, the changing levels of these metabolites in intact mouse bladders and cultured urothelial cells. These measurements will be correlated with assayed changes in mitochondrial enzyme functions.
Specific Aim 2 will test the hypothesis that the intravesical administration of NOS antagonists or MnSOD or SOD mimetics with peroxidase activity protect the bladder against radiation cystitis. The effectiveness of these therapies in irradiated mouse bladders will be assessed at 1 to 6 months by employing permeability measurements, cystometry and histochemical analyses for collagen deposition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071085-03
Application #
7240493
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$317,538
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ikeda, Youko; Zabbarova, Irina V; Birder, Lori A et al. (2018) Relaxin-2 therapy reverses radiation-induced fibrosis and restores bladder function in mice. Neurourol Urodyn 37:2441-2451
Zabbarova, Irina V; Ikeda, Youko; Carder, Evan J et al. (2018) Targeting p75 neurotrophin receptors ameliorates spinal cord injury-induced detrusor sphincter dyssynergia in mice. Neurourol Urodyn 37:2452-2461
Ikeda, Y; Zabbarova, I; Schaefer, C M et al. (2017) Fgfr2 is integral for bladder mesenchyme patterning and function. Am J Physiol Renal Physiol 312:F607-F618
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Tyagi, Pradeep; Kashyap, Mahendra; Yoshimura, Naoki et al. (2017) Past, Present and Future of Chemodenervation with Botulinum Toxin in the Treatment of Overactive Bladder. J Urol 197:982-990
Kullmann, F Aura; Clayton, Dennis R; Ruiz, Wily G et al. (2017) Urothelial proliferation and regeneration after spinal cord injury. Am J Physiol Renal Physiol 313:F85-F102
Ito, Hiroki; Pickering, Anthony E; Igawa, Yasuhiko et al. (2017) Muro-Neuro-Urodynamics; a Review of the Functional Assessment of Mouse Lower Urinary Tract Function. Front Physiol 8:49
Kanai, Anthony; Fry, Christopher; Ikeda, Youko et al. (2016) Implications for bidirectional signaling between afferent nerves and urothelial cells-ICI-RS 2014. Neurourol Urodyn 35:273-7
Hanna-Mitchell, Ann T; Wolf-Johnston, Amanda S; Barrick, Stacey R et al. (2015) Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn 34:79-84
Fry, Christopher H; Sahai, Arun; Vahabi, Bahareh et al. (2014) What is the role for biomarkers for lower urinary tract disorders? ICI-RS 2013. Neurourol Urodyn 33:602-5

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