Bladder decompensation and reduction in nerve density in a rat model of chronic bladder outlet obstruction is attenuated with the NLRP3 inhibitor glyburide.

Bladder outlet obstruction (BOO) leads to progressive voiding dysfunction. Acutely, obstruction triggers inflammation that drives bladder dysfunction. Over time, inflammation leads to decreased bladder nerve density and increased fibrosis that is responsible for eventual decompensation and irreversibility. We have previously shown that BOO triggers inflammation, reduced bladder nerve density and increased fibrosis via activation of the NLRP3 inflammasome in an acutely obstructed (12 day) rat model. However, as BOO progresses the bladder may become decompensated with an increase in post-void residual volume (PVR) and decreased voiding efficiency. Currently we have examined rat bladder function and nerve densities after chronic BOO to determine if NLRP3 plays a role in the decompensation at this stage. 4 groups were examined: control, sham-operated, BOO or BOO+gly (glyburide; an NLRP3 inhibitor). After 42 days, bladder weight, inflammation (Evan's blue), urodynamics and nerve density were measured. BOO greatly enhanced bladder weights and inflammation while inflammation was prevented by glyburide. Voiding pressures were increased and flow rates decreased in BOO and BOO+gly groups, demonstrating physical obstruction. No difference in frequency or voided volume (VV) were detected. However, PVRs were greatly increased in BOO rats while BOO+gly rats were not different than controls. Moreover, there was a dramatic decrease in voiding efficiency in the chronic BOO rats which was prevented with glyburide treatment. Finally, a reduction in nerve density was apparent with BOO and attenuated with glyburide. Together the results suggest a critical role for NLRP3 in mediating bladder decompensation and nerve density during chronic BOO.