MP60-01 MACROPHAGE MIGRATION INHIBITORY FACTOR AND TLR4 SIGNALING ARE INVOLVED IN PAR4-INDUCED PERSISTENT BLADDER PAIN

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP60-01 MACROPHAGE MIGRATION INHIBITORY FACTOR AND TLR4 SIGNALING ARE INVOLVED IN PAR4-INDUCED PERSISTENT BLADDER PAIN Shaojing Ye, Fei Ma, Dlovan F. D. Mahmood, and Pedro Vera Shaojing YeShaojing Ye More articles by this author , Fei MaFei Ma More articles by this author , Dlovan F. D. MahmoodDlovan F. D. Mahmood More articles by this author , and Pedro VeraPedro Vera More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Interstitial cystitis/Bladder pain syndrome is a painful condition with unknown etiology. Repeated intravesical PAR4 induced persistent bladder hyperalgesia (BHA) in mice that lasts several days after the last stimulus with little or no evidence of bladder inflammation. Our studies showed that spinal macrophage migration inhibitory factor (MIF) and High Mobility Group Box 1 (HMGB1) are critical causative factors. We aimed to dissect this persistent pain pathway and explore effective targets for treating persistent bladder pain. METHODS: Persistent BHA was induced in female mice (WT, TLR4 null, Trif null) by three intravesical instillations (days 0, 2 and 4) with PAR4 agonist (100 uM; 1hr, scrambled peptide as control) under anesthesia. Lower abdominal hypersensitivity was measured by von Frey filaments on days 0-4 and 7-9. Intraperitoneal treatment was performed on days 2-8 and included: ISO-1 (MIF antagonist); 10% DMSO; ethyl pyruvate (EP; inhibits HMGB1 release); and PBS. Awake micturition parameters (voided volume; frequency) were assessed on day 9. Bladder histology assessed inflammation/edema. R was used for all analyses. RESULTS: Inhibition of MIF activity with ISO-1 robustly reversed the PAR4-induced persistent BHA in WT mice (Figure 1A) while treatment with EP partially reduced BHA (Figure 1B). TLR4 deficiency substantially damped persistent pain (Figure 2A) while lack of Trif did not affect PAR4-induced persistent BHA (Figure 2B). No significant effects were noted on micturition volume, frequency, inflammation, or edema. CONCLUSIONS: MIF, HMGB1, and TLR4 signaling activation are required for PAR4-induced persistent BHA. However, Trif may not be critical for persistent bladder pain. Further dissecting TLR4 downstream signaling pathway is necessary to identify important mediators and whether they act centrally or peripherally. This may lead to the discovery of novel potential therapeutic targets to treat persistent bladder pain. Source of Funding: DK121695 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e842 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Shaojing Ye More articles by this author Fei Ma More articles by this author Dlovan F. D. Mahmood More articles by this author Pedro Vera More articles by this author Expand All Advertisement PDF downloadLoading ...