Neurochemical expression and function of interstitial cells (ICs) in the urinary bladder of mice with cyclophosphamide (CYP)-induced cystitis
Conference Year
January 2019
Abstract
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful, debilitating lower urinary tract (LUT) disorder characterized by pelvic pain and increased urinary frequency. Bladder overactivity is a hallmark of IC/BPS; however, the exact etiology of IC/BPS is still unknown. We have recently begun to characterize a population of interstitial cells (ICs) in the lamina propria (LP) of mouse bladder that express PDGFRα- and TRPV4-immunoreactivity (IR) and exhibit increased Ca2+ activity in response to TRPV4 agonist. ICs have been implicated in contributing to bladder pathophysiology including detrusor overactivity. Reductions in detrusor overactivity following spinal cord injury have been reported with imatinib, an inhibitor of PDGFR-α signaling. Using a mouse model of CYP-induced bladder inflammation, we now demonstrate increases in PDGFRα- and TRPV4-IR and transcripts in ICs in the LP. We hypothesize that ICs in the LP contribute to increased voiding frequency observed with CYP-induced cystitis. We examined the functional role of ICs using a tyrosine kinase inhibitor, imatinib mesylate, with acute (4 hr) CYP-induced cystitis as a model of IC/BPS. In these experiments, mice were treated with imatinib (200-250 mg/kg; gavage) for six, consecutive days. On the third day, we surgically implanted a bladder catheter to evaluate bladder function using conscious cystometry. On the sixth day, mice were treated (4 hr) acutely with CYP (200 mg/kg; i.p.) and bladder function was then evaluated with continuous intravesical instillation of room temperature saline. We evaluated various imatinib doses (50-250 mg/kg) and delivery routes (chronic oral gavage, chronic intraperitoneal injection, acute intravesical instillation) of imatinib. We have determined that imatinib (200-250 mg/kg) delivered by oral gavage is the most effective dosage and route, of those evaluated, in reducing effects of acute CYP treatment. Acute (4 hr) CYP treatment in mice (male and female) significantly (p = 0.0025) reduced bladder capacity and intermicturition interval with minimal effects on bladder pressures. Oral gavage of imatinib mesylate (200-250 mg/kg), in female mice with CYP-induced (4 hr) cystitis, significantly increased intermicturition intervals (p = 0.0005) and bladder capacity (p < 0.0001) compared to mice treated with CYP-induced (4 hr) cystitis and saline gavage. However, these changes were not observed in male mice treated with CYP. Interestingly, control (no CYP) mice treated with imatinib (200-250 mg/kg; gavage), exhibited significantly decreased intermicturition intervals (male: p = 0.0467) and bladder capacity (male: p = 0.0016; female: p = 0.0136) compared to control mice (no CYP) and saline gavage. Effects of imatinib on bladder pressure (e.g., maximum, minimum, threshold) are also being evaluated in CYP-treated and control (no CYP) mice. In conclusion, imatinib (200-250 mg/kg; gavage) significantly increased bladder capacity and intermicturition intervals in female mice treated acutely (4 hr) with CYP suggesting that imatinib may be an effective treatment to improve bladder function following urinary bladder inflammation. In addition, these results demonstrate differential effects of imatinib on mouse bladder function depending on the presence of bladder inflammation (CYP vs. control). Future studies will investigate changes in inflammatory mediators that may underlie a mechanism of action of imatinib in the LUT.
Primary Faculty Mentor Name
Margaret Vizzard
Faculty/Staff Collaborators
Beatrice Girard (Research Scientist) Susan Campbell (Lab Manager)
Status
Graduate
Student College
Graduate College
Program/Major
Neuroscience
Primary Research Category
Biological Sciences
Secondary Research Category
Health Sciences
Neurochemical expression and function of interstitial cells (ICs) in the urinary bladder of mice with cyclophosphamide (CYP)-induced cystitis
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a painful, debilitating lower urinary tract (LUT) disorder characterized by pelvic pain and increased urinary frequency. Bladder overactivity is a hallmark of IC/BPS; however, the exact etiology of IC/BPS is still unknown. We have recently begun to characterize a population of interstitial cells (ICs) in the lamina propria (LP) of mouse bladder that express PDGFRα- and TRPV4-immunoreactivity (IR) and exhibit increased Ca2+ activity in response to TRPV4 agonist. ICs have been implicated in contributing to bladder pathophysiology including detrusor overactivity. Reductions in detrusor overactivity following spinal cord injury have been reported with imatinib, an inhibitor of PDGFR-α signaling. Using a mouse model of CYP-induced bladder inflammation, we now demonstrate increases in PDGFRα- and TRPV4-IR and transcripts in ICs in the LP. We hypothesize that ICs in the LP contribute to increased voiding frequency observed with CYP-induced cystitis. We examined the functional role of ICs using a tyrosine kinase inhibitor, imatinib mesylate, with acute (4 hr) CYP-induced cystitis as a model of IC/BPS. In these experiments, mice were treated with imatinib (200-250 mg/kg; gavage) for six, consecutive days. On the third day, we surgically implanted a bladder catheter to evaluate bladder function using conscious cystometry. On the sixth day, mice were treated (4 hr) acutely with CYP (200 mg/kg; i.p.) and bladder function was then evaluated with continuous intravesical instillation of room temperature saline. We evaluated various imatinib doses (50-250 mg/kg) and delivery routes (chronic oral gavage, chronic intraperitoneal injection, acute intravesical instillation) of imatinib. We have determined that imatinib (200-250 mg/kg) delivered by oral gavage is the most effective dosage and route, of those evaluated, in reducing effects of acute CYP treatment. Acute (4 hr) CYP treatment in mice (male and female) significantly (p = 0.0025) reduced bladder capacity and intermicturition interval with minimal effects on bladder pressures. Oral gavage of imatinib mesylate (200-250 mg/kg), in female mice with CYP-induced (4 hr) cystitis, significantly increased intermicturition intervals (p = 0.0005) and bladder capacity (p < 0.0001) compared to mice treated with CYP-induced (4 hr) cystitis and saline gavage. However, these changes were not observed in male mice treated with CYP. Interestingly, control (no CYP) mice treated with imatinib (200-250 mg/kg; gavage), exhibited significantly decreased intermicturition intervals (male: p = 0.0467) and bladder capacity (male: p = 0.0016; female: p = 0.0136) compared to control mice (no CYP) and saline gavage. Effects of imatinib on bladder pressure (e.g., maximum, minimum, threshold) are also being evaluated in CYP-treated and control (no CYP) mice. In conclusion, imatinib (200-250 mg/kg; gavage) significantly increased bladder capacity and intermicturition intervals in female mice treated acutely (4 hr) with CYP suggesting that imatinib may be an effective treatment to improve bladder function following urinary bladder inflammation. In addition, these results demonstrate differential effects of imatinib on mouse bladder function depending on the presence of bladder inflammation (CYP vs. control). Future studies will investigate changes in inflammatory mediators that may underlie a mechanism of action of imatinib in the LUT.