Date of Award
Doctor of Philosophy (PhD)
Margaret A. Vizzard
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a condition of lower urinary tract (LUT) dysfunction, characterized by 6 ≤ weeks of LUT symptoms and pelvic pain or discomfort, with other discernable causes excluded. Few treatments exist and more therapeutic targets are needed. Progress is further compounded by the unknown etiology of IC/BPS.
A subpopulation of interstitial cells has been recently identified in the urinary bladder detrusor muscle and lamina propria (LP) and many express the platelet-derived growth factor receptor alpha (PDGFRα). Functionally, LP interstitial cells are theorized to act as intermediary sensors, transducing signals from the urothelium to the detrusor and/or nerves, and the detrusor interstitial cells are theorized to regulate smooth muscle excitability. Reports suggest urinary bladder interstitial cells may contribute to LUT dysfunction; PDGFRα+ interstitial cells demonstrate altered chemical expression and electrophysiological activity and are associated with bladder hyperactivity in human patients and animal models with IC/BPS or OAB. Imatinib mesylate is a tyrosine kinase inhibitor of the PDGFRα and -β, c-KIT, and BCR-ABL tyrosine kinases, and has been previously used in the LUT to disrupt interstitial cell function. In models of LUT dysfunction, imatinib has been shown to reduce interstitial cell marker expression, detrusor contractile properties, and improve bladder function.
We hypothesize that urinary bladder PDGFRα interstitial cells contribute to bladder dysfunction (e.g., decreased voiding frequency, decreased infused volume, increased somatic sensitivity) by altering the inflammatory milieu of the micturition reflex components (e.g., urinary bladder). In the first aim of this dissertation, we investigated the effect of imatinib on functional LUT outcomes with a prevention and treatment design, in a mouse model of cyclophosphamide (CYP)-induced cystitis. These studies suggest that imatinib administration, by prevention or treatment, improves cystometric LUT outcomes, but does not affect somatic sensitivity, in mice with acute CYP-induced cystitis. In the second aim of this dissertation, we investigated potential mechanism(s) of action by which imatinib mediates LUT improvements in acute CYP-induced cystitis. These studies suggest (1) imatinib prevention reduces urinary bladder inflammatory mediator expression, (2) imatinib treatment acts by other, non-immune mediated mechanism(s) or affects mediators other than those examined, and (3) imatinib prevention and treatment reduces LP phosphorylated kinase expression in mice with acute CYP-induced cystitis. Collectively, these studies characterize the effects of imatinib on LUT at the functional and cellular level, by two experimental designs, in a mouse model of CYP-induced cystitis, and demonstrate pre-clinical evidence, supporting imatinib as a potential therapeutic option for LUT dysfunction. Ultimately, this work furthers our understanding of imatinib mesylate on urinary bladder function, inflammatory mediators and signaling mechanisms in a mouse model of CYP-induced cystitis.
Number of Pages
Perkins, Megan Elizabeth, "Effects Of Imatinib Mesylate On Urinary Bladder Function And Inflammatory Mediators In Mice With Cyclophosphamide-Induced Cystitis" (2022). Graduate College Dissertations and Theses. 1575.