Bladder outlet obstruction (BOO) is common in people as they age due to conditions such as benign prostatic hyperplasia. BOO causes lower urinary tract symptoms (LUTS) that are usually progressive and can lead to urinary incontinence and even renal failure over time. Current therapies are not always effective at preventing this progression and millions of people suffer from bothersome symptoms that have been shown to significantly decrease quality of life. This study presents a paradigm shift in our understanding and potential treatment of BOO by focusing on the inflammation evoked by elevated pressures secondary to increased resistance to urinary outflow. This work springs from the discovery in 2002 of supra-molecular structures, known as inflammasomes, which are formed from Nod-like receptors in response to pathogenic stimuli and also in the setting of sterile inflammation such as is found during BOO. Specifically, NLRP3 is thought to be the mediator of sterile inflammation. Inflammasomes trigger inflammation by causing the maturation and release of IL-1 and IL-18, two central pro- inflammatory cytokines. While the role of inflammasomes has been elucidated in other organ systems and disease states, their function in the urinary tract has only recently been investigated. Our group was the first to localize them to the urothelium and characterize NLRP3 as playing a central role in the setting of cyclophosphamide-induced cystitis, a well-studied model of sterile inflammation in the bladder. In this proposal, we test te hypothesis that elevated pressure caused by BOO activates NLRP3 in the urothelia and initiates bladder inflammation. In turn, the inflammatory response leads to LUTS and fibrosis which corresponds to the clinical deterioration seen in this pathological state. We will also determine i NLRP3 activation causes phenotypic changes in the urothelium which provoke further bladder dysfunction. Our preliminary data strongly suggests that inhibition of NLRP3 in BOO rats considerably diminishes the deleterious effects on the bladder that are normally seen with obstruction.
In Aim 1 we will demonstrate that NLRP3 in a urothelial cell line (MYP3) is activated in response to pressure and we will probe the mechanism by which this occurs.
Aim 2 is an in vivo study in rats that will allow us to define the role that NLRP3 plays in the development of inflammation, altered urothelial signaling, voiding dysfunction, fibrosis and renal impairment during BOO. Using an FDA-approved medication, glyburide, as the NLRP3 inhibitor in Aim 2 gives this project strong translational potential as this could provide immediate benefit to patients suffering from BOO.
Bladder outlet obstruction produced by conditions such as benign prostatic hyperplasia, causes progressive lower urinary tract symptoms in people as they age. Progression of this pathology is dependent upon inflammatory and fibrotic changes in the bladder which is a non-infectious form of cystitis. This study will define inflammasomes as the mediators of pressure-induced bladder damage and use an FDA-approved inflammasome inhibitor (glyburide) to block these deleterious effects, giving this proposal a strong translationl potential.
