Hyperinnervation and Chronic Mast Cell Activity in Bladder Pain Syndrome

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Bladder Pain Syndrome (BPS) is a broad-spectrum pelvic pain disorder, characterized by pain and at least one underlying lower urinary tract symptom, that affects millions in the US. Despite its prevalence, the underlying etiology is unknown. Several clinical findings point to a potential role of peripheral nerves in the bladder, such as hyperinnervation and increased urinary nerve growth factor (NGF) in BPS patients. In addition, mast cell (MC) hyperplasia and a history of recurrent urinary tract infections (recUTIs) is also observed. Based on the similar findings of elevated urinary NGF in recUTI patients and the prominent role of MCs in bladder immunity to UTI, we examined whether mice that experience multiple UTIs develop BPS symptoms. We found that mice subjected to multiple bacterial bladder infections experienced both pelvic hypersensitivity and bladder frequency, assayed by mechanical stimulation of the pelvic region and cystometric analysis, respectively. These pathological outcomes were linked to extensive hyperinnervation, specifically in sensory nociceptive nerves in the bladder lamina propria, induced by recruited NGF-producing CCR2+ Ly6Chigh inflammatory monocytes and to the presence of activated MCs near sprouting nerves. Notably, both CCR2-/- and MC-deficient mice each were protected from developing BPS symptoms after multiple infections. Lastly, the MC product histamine was sufficient to trigger both hypersensitivity and frequency in a TRPV1 dependent manner. Taken together, these findings reveal chronic MC activity in a hyperinnervated bladder, triggered by past infections, could be an underlying basis for BPS.







Hayes, Byron (2021). Hyperinnervation and Chronic Mast Cell Activity in Bladder Pain Syndrome. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23072.


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