Role of Protease-Activated Receptor 2 in the development of lower urinary tract dysfunction - Beyond the Abstract

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating disease that is characterized by chronic pain originating from multiple pelvic organs (prostate, perineum, rectum, penis, and testicles) and is accompanied by lower urinary tract symptoms (urgency and frequency) (1,2). CP/CPPS patients report a negative impact on the quality of life due to the severity of symptoms (3,4). However, current treatment options for CP/CPPS symptoms are dependent on limited studies that show a lack of long-term benefits (5,6). Therefore, discovery of a novel therapeutic target is imperative to treat symptoms associated with CP/CPPS.

Previous studies have shown that the expressed prostatic secretions (EPS) collected from patients with CP/CPPS exhibit higher levels of mast cell tryptase in comparison to a healthy population (7). We have published data that revealed a link between tryptase activation of the protease-activated receptor 2 (PAR2) and severity of pelvic allodynia (pain originating from the pelvic region) in a mouse model of CP/CPPS, called experimental autoimmune prostatitis (EAP) (7). However, the role of tryptase mediated PAR2 activation (trytpase-PAR2 axis) on lower urinary tract dysfunction is unclear. We therefore hypothesized that PAR2 is involved in the sustainability of both pelvic chronic pain and lower urinary dysfunction and that therapeutic inhibition of PAR2 would blunt the progression of these symptoms.

In the current study, we show that mice (C57BL/6J) with EAP develop aberrant urodynamics (increased voiding rate and decreased bladder compliance) at day 30 in comparison to naive cohorts. The histological and immunobot data showed that fibrosis of the prostate and bladder in mice with EAP at day 30 contributed to the alteration in our cystometric recordings. Moreover, we highlighted the importance of PAR2 in our model by demonstrating that PAR2 deficient mice (PAR2-KO) with EAP do not develop lower urinary tract dysfunction at day 30 and have reduced fibrosis markers in the prostate and the bladder. We also demonstrated that PAR2-KO mice with EAP show diminished levels of chronic inflammation in the prostate suggesting that persistent inflammation due to tryptase-PAR2 activation may be required for the induction of fibrosis. However, the fact that PAR2-KO did not develop lower urinary tract dysfunction provides little evidence regarding the clinical application of PAR2 inhibition.  Thus, we hypothesized that inhibition of PAR2 after induction of EAP will reverse both tactile allodynia and lower urinary tract dysfunction at day 30.

To demonstrate that early intervention (at day 10) with a PAR2 neutralizing antibody (SAM-11) can mitigate the progression of tactile allodynia and lower urinary dysfunction in mice with EAP, mice with EAP received systemic (intraperitoneal) injections of SAM-11 every four days until day 30. We found no development of either pain or lower urinary dysfunction at day 30 between in mice with EAP that received SAM-11 treatment. These results suggest that prolonged inhibition of the tryptase-PAR axis may have beneficial effects in the treatment of symptoms associated with CP/CPPS.

Although our results show that PAR2 inhibition leads to marked improvement in pain and lower urinary tract dysfunction, our study did not address whether treatment with SAM-11 is effective after day 30. Nevertheless, published work suggests that SAM-11 treatment (initiated at day 30) blunts pelvic allodynia in mice with EAP at day 45 but the effect on lower urinary tract dysfunction is unknown (7).

In summary, this study showed that:

1) lower urinary tract dysfunction can be demonstrated in a chronic model of CP/CPPS (EAP) and is associated with the development of fibrosis in the prostate and the bladder

2) deficiency in the PAR2 receptor inhibits the development of fibrosis and lower urinary tract dysfunction in EAP

3) therapeutic inhibition of tryptase-PAR2 signaling can successfully treat pain and lower urinary bladder dysfunction. 

These results suggest that PAR2 is a potential target for treating pelvic allodynia and urinary voiding dysfunction in a model of CP/CPPS.

Written By:

Kenny Roman1, Stephen F Murphy1, Joseph D. Done1, Kevin E. McKenna2, Anthony J. Schaeffer1 and Praveen Thumbikat1, 3
1Departments of Urology, 2Physiology, 3Pathology,
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA


1. Schaeffer, A. J., Datta, N. S., Fowler, J. E., Jr., Krieger, J. N., Litwin, M. S., Nadler, R. B., Nickel, J. C., Pontari, M. A., Shoskes, D. A., Zeitlin, S. I., and Hart, C. (2002) Urology 60, 1-4
2. Daniels, N. A., Link, C. L., Barry, M. J., and McKinlay, J. B. (2007) Journal of the National Medical Association 99, 509-516
3. Tripp, D. A., Nickel, J. C., Shoskes, D., and Koljuskov, A. (2013) World journal of urology 31, 733-739
4. Clemens, J. Q., Brown, S. O., and Calhoun, E. A. (2008) The Journal of urology 180, 1378-1382
5. Wang, J., Yan, D., Liang, K., and Xu, Z. (2016) International urology and nephrology 48, 13-18
6. Anderson, R. U., and Nathanson, B. H. (2011) Nature reviews. Urology 8, 236-237
7. Roman, K., Done, J. D., Schaeffer, A. J., Murphy, S. F., and Thumbikat, P. (2014) Pain 155, 1328-1338

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