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.
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