INTRODUCTION AND OBJECTIVES: Partial bladder outlet obstruction (pBOO) results in a progression of pathophysiologic changes. The observed compensatory response results in smooth muscle hypertrophy, and the development of myofibroblasts. This is followed by a decompensatory phase, whereby the bladder becomes fibrotic, and the loss of tissue compliance results in markedly elevated bladder pressures. We hypothesize that the stress of pBOO results in an inflammatory response, and this results in muscle hypertrophy and eventually fibrosis. To investigate this we utilized an animal model with physiologically relevant pBOO, and examined the progression of urodynamic changes, as well as histologic and biochemical end-points over a prolonged period of pBOO.

METHODS: Female rats underwent surgical induction of pBOO for either 2,4,8, or 13 weeks and compared to shams. Urodynamic measurements were used to compare bladder volumes and pressure. Tissue was grossly analyzed with light microscopy and bladder weights and thicknesses were compared. RT-PCR for collagen, TGF-B, CTGF, HIF-1a, and PDGF-A was performed on all samples, as well as immunohistochemistry for a-SMA. Finally, mass spectrometry was used to quantify the collagen content of the bladders as a measure of fibrosis.

RESULTS: Urodynamics demonstrated an initial increase in capacity while maintaining normal pressures, but then deteriorated into small capacity, high-pressure bladders. H+E demonstrated an initial inflammatory response, and this was confirmed with significantly increased mRNA levels of TGF-B, CTGF, HIF-1a, and PDGF. The progression to smooth muscle hypertrophy was evident on H+E and confirmed with increased bladder mass and thickness. IHC for a-sma demonstrate the increase in myofibroblasts associated with the increased bladder pressures. Masson’s Trichrome and mass spectrometry showed an increase in collagen.

CONCLUSIONS: With this model, we have effectively replicated the distinct clinical phases of bladder decompensation after pBOO. The time course of the inflammatory markers implicates their role in this process and implies the need for early intervention to prevent this cascade. Novel strategies targeting these observed physiologic responses could lead to preventative therapeutic strategies warranting further exploration. In addition, the resulting end-stage bladder model allows for the potential investigation of tissue-engineered bladder substitutes.

Source of Funding: Northern Alberta Urology Foundation
Edmonton Civic Employees
Stollery CHildren's Hospital Foundation