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Mechanisms of oxidative stress in interstitial cystitis/bladder pain syndrome

Nature Reviews Urology (2024)Cite this article

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Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by bladder and/or pelvic pain, increased urinary urgency and frequency and nocturia. The pathophysiology of IC/BPS is poorly understood, and theories include chronic inflammation, autoimmune dysregulation, bacterial cystitis, urothelial dysfunction, deficiency of the glycosaminoglycan (GAG) barrier and urine cytotoxicity. Multiple treatment options exist, including behavioural interventions, oral medications, intravesical instillations and procedures such as hydrodistension; however, many clinical trials fail, and patients experience an unsatisfactory treatment response, likely owing to IC/BPS phenotype heterogeneity and the use of non-targeted interventions. Oxidative stress is implicated in the pathogenesis of IC/BPS as reactive oxygen species impair bladder function via their involvement in multiple molecular mechanisms. Kinase signalling pathways, nociceptive receptors, mast-cell activation, urothelial dysregulation and circadian rhythm disturbance have all been linked to reactive oxygen species and IC/BPS. However, further research is necessary to fully uncover the role of oxidative stress in the pathways driving IC/BPS pathogenesis. The development of new models in which these pathways can be manipulated will aid this research and enable further investigation of promising therapeutic targets.

Key points

  • Interstitial cystitis/bladder pain syndrome (IC/BPS) has neither a known exact cause nor a definitive cure, and no FDA-approved treatment has been introduced since 1996.

  • Studies suggest that various molecular pathways are involved in IC/BPS, including the JUN N-terminal kinase (JNK) pathway, transient receptor potential (TRP) channels, activated mast cells, mucosal signalling, circadian rhythm regulation, inflammation and neural dysregulation.

  • Reactive oxygen species are a common factor in different molecular pathways and channels implicated in IC/BPS.

  • Current animal model systems do not fully recapitulate the pathophysiological conditions in human IC/BPS, and targeting specific molecular pathway disruption in animal models might serve as a better option than existing models.

  • As IC/BPS might be multifactorial, future research should target different implicated pathways simultaneously and study the role of reactive oxygen species as a root cause in IC/BPS.

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Fig. 1: Proposed pathological mechanisms of IC/BPS.
Fig. 2: Animal models of IC/BPS.

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Acknowledgements

A.D.D. and A.M. have received support from the McCormick and Gabilan Faculty Fellowship Award (SPO 272363) and the National Institutes of Health (NIH 1R01DK134989). A.D.D. has also received support from the National Institutes of Health (NIH 2R44DK127580, NIH 1R01CA249807) and California Institute of Regenerative Medicine (CIRM DISC2-13205).

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  1. Department of Urology, Stanford University School of Medicine, Palo Alto, CA, USA

    Ashu Mohammad, Chen Shenhar & Amy D. Dobberfuhl

  2. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Mallory A. Laboulaye

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Mohammad, A., Laboulaye, M.A., Shenhar, C. et al. Mechanisms of oxidative stress in interstitial cystitis/bladder pain syndrome. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-023-00850-y

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