ROLE OF ISCHEMIA IN BLADDER OVERACTIVITY AND FIBROSIS
Principal Investigator: MIKE SIROKY
Abstract: Lower urinary tract symptoms (LUTS) in aging men are commonly ascribed to bladder outflow obstruction (BOO). However, pressure-flow studies have shown that, in approximately one-third of cases, these symptoms are not associated with BOO and suggest that LUTS in the elderly are not necessarily related to BOO or specific to the male gender. Rather, it is likely that LUTS is related to detrusor instability, impaired detrusor contractility or both. Recent evidence of correlation between vascular risk factors and the development of LUTS suggests that impairment of bladder blood flow and concomitant ischemic changes in the bladder may play a role. Our clinical studies showed that a variety of procedures including bladder filling and removal of the prostate lead to significant ischemia of human bladder. Our studies with an animal model showed that chronic bladder ischemia produces marked functional and structural changes including bladder overactivity, abnormal smooth muscle reactivity, non-compliance, disruption of urothelium and fibrosis. These ischemic changes in the bladder were associated with overproduction of eicosanoids, leukotrienes, thromboxane A2 (TXA2) and transforming growth factor beta 1 (TGFbeta1) and oxidative stress. The mechanisms of ischemia-induced bladder dysfunction have not been previously investigated. Based on our preliminary observations we hypothesize that ischemia plays an important role in functional and structural changes of the bladder as well as in LUTS. The mechanism of ischemia-induced detrusor overactivity involves the cyclooxygenase and lipoxygenase products, oxidative stress and overproduction of oxygen free radicals and structural and ultrastructural changes in the cellular and subcellular components of the detrusor wall. The mechanism of ischemia-induced bladder fibrosis involves increased production of TXA2 and TGFbeta1, which in turn leads to deposition of connective tissue and smooth muscle atrophy. The aims of our proposal are: 1) To study correlation of human bladder dysfunction and LUTS with changes in bladder blood flow. 2) To study the roles of eicosanoids, leukotrIenes and the cyclooxygenase and lipooxygenase pathways in chronic ischemia-induced detrusor overactivity. 3) To study the roles of oxidative stress and oxygen free radicals in chronic ischemia-induced detrusor overactivity. 4) To study whether chronic ischemia-induced detrusor overactivity is related to ultrastructural changes in the cellular and subcellular components of the bladder wall. 5) To study the cellular and molecular mechanisms by which chronic ischemia causes bladder fibrosis and non-compliance. Our proposed studies may lead to a better understanding of the cellular and molecular mechanisms of detrusor overactivity, non-compliance and fibrosis. Such enhanced understanding may lead to more effective diagnosis, treatment and perhaps even prevention of these problems.
Funding Period: 2000-09-01 - 2005-08-31
more information: NIH RePORT