A precise characterization of mechanism behind various painful bladder syndromes remains elusive. One potential mechanism may involve modulation of local prostaglandin (PG) synthesis. It is established that bladder is an independent site of PG synthesis in response to distention, inflammation and mucosal trauma, and there is compelling evidence that bladder PGs play a critical role in the regulation of bladder smooth muscle contractility, micturition neural reflexes, and urothelial cytoprotection. It has been demonstrated that a key rate-limiting enzymatic step in PG biosynthesis, cyclooxygenase (COX), exists in two distinct isoforms, each with differential pattern of gene expression and biological function. In particular, the inducible isoform, COX-2, has been shown to be important in the regulation of various inflammatory and proliferative conditions. In this proposal we intend to investigate the role played by COX-2 gene activation in the pathogenesis of bladder instability and tissue proliferation, as well as to further examine the regulatory mechanism of COX-2 gene expression in bladder cells using an outlet obstruction model. The impetus for our proposal is based on a hypothesis that upregulation of COX-2 gene expression in bladder disease processes (such as bladder outlet obstruction and inflammation) leads to increased local synthesis of PGs, which in turn promote the development of bladder pain, instability, and tissue proliferation. We have demonstrated previously that COX-2 gene expression is activated specifically in the bladder smooth muscle cells (SMC) after outlet obstruction via increased mechanical stretch. We therefore plan to (1) investigate the specific role of COX-2 gene activation in the regulation of altered bladder contractility after partial obstruction, (2) examine the role of COX-2 gene activation after stretch (i.e., obstruction) in the regulation of bladder SMC proliferation, and (3) determine the intracellular signaling mechanisms and the potential downstream targets of COX-2 gene expression in bladder SMC after stretch. It has been demonstrated in other organ systems that COX-2 specific inhibitors can reduce inflammation and pain more precisely and effectively than traditional non-isoform specific COX inhibitors. Therefore, characterizing the biological role of PG synthetic pathways via COX-2 gene activation in bladder should lead to novel insights in the overall management of painful bladder syndromes.
