Acute and chronic inflammation is a common finding in the adult prostate that has been implicated in the genesis of lower urinary tract symptoms (LUTS) in aging men. The strong association has generated considerable interest in prostate inflammation and its potential as a therapeutic target to prevent or treat LUTS. We and others have postulated that prostatic inflammation contributes to development of LUTS in two ways: (1) producing irritative voiding symptoms by effects on afferent nerves co-innervating the prostate and bladder and (2) producing obstructive voiding symptoms by inducing fibrosis in the prostate. We will perform a retrospective analysis of surgically treated patients who underwent detailed preoperative urodynamic evaluation to examine the association of inflammation with fibrosis. To test the hypothesis that inflammation produces irritative symptoms, we will examine the correlation of inflammation with detrusor overactivity. To test the hypothesis that fibrosis produces obstruction, we will examine the correlation between if fibrosis and increased urethral resistance. This analysis will provide the first comprehensive assessment correlating inflammation and fibrosis and their individual associations with changes in bladder function that are the hallmark of BPH/LUTS. We will perform mechanistic studies using an established mouse model of prostatic inflammation in which we have shown that inflammation induces a significant increase in voiding frequency and prostatic fibrosis. We will determine whether increased voiding frequency is associated with detrusor overactivity due to changes in motor nerve activity and/or cholinergic sensitivity of the detrusor and the role of epigenetic regulation in the fibrotic response. We will then examine the reversibility abnormal voiding behavior and prostate fibrosis when inflammation subsides.
Three specific aims examine the hypothesis that prostatic inflammation causes urinary frequency by producing detrusor overactivity and causes bladder outlet obstruction by inducing prostatic fibrosis.
Specific Aim 1. Determine the association of transition zone inflammation and fibrosis with detrusor overactivity and increased urethral resistance in men with BPH/LUTS.
Specific Aim 2. Test the hypothesis that chronic prostate inflammation induces detrusor overactivity and increased voiding frequency.
Specific Aim 3. Test the hypothesis that prostatic fibrosis associated with chronic inflammation is reversible.

Public Health Relevance

The goal of our research is to understand the cause of benign prostate hyperplasia and lower urinary tract symptoms (BPH/LUTS) in aging men. BPH/LUTS is a prevalent condition among aging men in general but recent studies show an even higher incidence among Veterans and, in addition, a significant association with PTSD. Despite being a major health issue for Veterans, a recent Veterans Administration study reveals that most Veterans with BPH/LUTS are not being treated properly. In part, this is attributable to the complex nature of BPH/LUTS and failure of primary physicians to offer appropriate treatment. We expect our research to provide important new insight into the development of BPH/LUTS and its treatment. The result will be to provide tools for the primary physician to confidently select the best treatment for each patient.

Agency
National Institute of Health (NIH)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX003454-01
Application #
9140679
Study Section
Surgery (SURG)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Wm S. Middleton Memorial Veterans Hosp
Department
Type
DUNS #
086683091
City
Madison
State
WI
Country
United States
Zip Code
53705