The mouse cyclophosphamide model of bladder pain syndrome: tissue characterization, immune profiling, and relationship to metabotropic glutamate receptors

Abstract

Painful bladder syndrome/Interstitial cystitis (PBS/IC) is a chronic disorder characterized clinically by recurring episodes of pelvic pain and increased urination frequency, significantly impairing patients' quality of life. Despite this, there is an unmet medical need in terms of effective diagnostics and treatment. Animal models are crucial in this endeavor. Systemic chronic administration of cyclophosphamide (CYP) in mice has been proposed as a relevant preclinical model of chronic bladder pain. However, molecular mechanisms underlying the pathogenesis of this model are lacking. Here, we show that mice, subjected to repetitive systemic injections of CYP, developed mild inflammatory response in bladder tissue characterized by submucosal edema, moderate increase in proinflammatory cytokine gene expression, and mastocytosis. No signs of massive inflammatory infiltrate, tissue hemorrhages, mucosal ulcerations and urothelium loss were observed. Instead, CYP treatment induced urothelium hyperplasia, accompanied by activation of proliferative signaling cascades, and a decrease in the expression of urothelium‐specific markers. Metabotropic glutamate (mGlu) receptors have been implicated in chronic pain disorders. CYP administration induced differential changes in mGlu receptors mRNA levels in bladder tissue, without affecting gene expression at spinal cord level, pointing to the potential link between peripheral mGlu receptors and inflammation‐induced bladder malfunction and hyperalgesia. Taken together, these data indicate that chronic CYP treatment in mice is a model of PBS mostly relevant to the major, nonulcerative subtype of the syndrome, characterized by a relatively unaltered mucosa and a sparse inflammatory response. This model can help to elucidate the pathogenetic mechanisms of the disease.

Stress and Chronic Pelvic Pain

“…165 Expression of metabotropic glutamate receptors were also upregulated primarily in bladder, rather than lumbosacral spinal cord, of mice with CYP-cystitis. 166 Together, these studies suggest that while there are etiological similarities between IBS and IC/PBS, the specific molecular mechanisms contributing towards bladder pain are likely distinct from those contributing towards the more predominantly studied gastrointestinal pain syndromes.…”

A novel role for follistatin in hypersensitivity following cystitis

“…This timing indicates that follistatin may also play a role in the maintenance of bladder hypersensitivity following chronic CYP‐induced cystitis. Previous studies demonstrated that acute or chronic CYP treatment can increase gene and protein expression of various other cytokines within 48 hr . These cytokines could contribute to inflammation resulting in the histological damage found on d6.…”

“…Previous studies demonstrated that acute or chronic CYP treatment can increase gene and protein expression of various other cytokines within 48 hr. [15][16][17][18][19][20][21][22] These cytokines could contribute to inflammation resulting in the histological damage found on d6. However, preliminary screening of several prototypical pro-and anti-inflammatory cytokines, including TGFb family members TGFb and InhbA, did not reveal any significant changes in gene expression on d6 (data not shown).…”

Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research

“…Direct immunosuppression: depletion of CD8+ resident DCs in murine spleen and lymph nodes, with subsequent decrease in Treg suppressive function; neutropenia; depletion of suppressor or regulatory T cells in diabetic NOD mice. [266][267][268][269][270][271][272][273]200 Other: enhanced antitumor efficacy by promoting proliferation/activation of adoptively transferred B and T cells after CYP-induced lymphodepletion in mice; reduced diversity of the fecal microbiota; hemorrhagic cystitis in C57BL/6 and DBA/2 mice; chronic cystitis in DBA/2 (CYP model of bladder pain syndrome); short root lengths and early apical foramen closure during molar root development in ICR mice; suppressed osteoblastogenesis and osteoclastogenesis in C57BL/6 male mice.…”