PD11-04 LOSS OF OSTEOPONTIN LEADS TO THE RESOLUTION OF E. COLI-INDUCED PROSTATIC INFLAMMATION AND FIBROSIS

Abstract

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-04 LOSS OF OSTEOPONTIN LEADS TO THE RESOLUTION OF E. COLI-INDUCED PROSTATIC INFLAMMATION AND FIBROSIS Petra Popovics, Asha Jain, Francesca Van, Hannah Ruetten, Mark Cadena, Kristen S. Uchtmann, Chad M. Vezina, and William A. Ricke Petra PopovicsPetra Popovics More articles by this author , Asha JainAsha Jain More articles by this author , Francesca VanFrancesca Van More articles by this author , Hannah RuettenHannah Ruetten More articles by this author , Mark CadenaMark Cadena More articles by this author , Kristen S. UchtmannKristen S. Uchtmann More articles by this author , Chad M. VezinaChad M. Vezina More articles by this author , and William A. RickeWilliam A. Ricke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men, but the molecular mechanism is unknown. We previously established that osteopontin (OPN), a pro-fibrotic cytokine, is more abundant in the prostate of men with LUTS compared to prostate tissue with normal histology. We also identified that OPN secretion is stimulated by inflammatory cytokines in prostate stromal cells and hypothesized that OPN exacerbates the prostatic inflammatory environment. The current study investigates whether the lack of OPN ameliorates inflammation-induced prostatic fibrosis and urinary dysfunction in mice following transurethral instillation of E. coli. METHODS: Uropathogenic Escherichia coli (UTI89) or saline (control) was instilled via a transurethral catheter (OD 0.8, 100 ul) two times, 3 days apart to C57BL/6J (WT) or B6.129S6(Cg)-Spp1tm1Blh/J (OPN-KO) mice. Urinary function was assessed by weekly void spot assays (VSA). Prostatic collagen was visualized with picrosirius red (PSR) staining and inflammation by immunohistochemistry of the pan-leukocyte marker CD45. RNA-Seq analysis was performed from the ventral prostate lobe. RESULTS: Urinary frequency significantly increased (2.05-fold, p=0.0097) 33 days after E. coli instillation in WT but not in OPN-KO mice. One week after infection, the ventral and dorsal prostate lobes were significantly inflamed (more CD45 cells) and collagen fibers were thicker in both WT and OPN-KO mice. In contrast, 2 months after instillation, OPN-KO mouse prostates contained significantly less total collagen and inflammation compared to WT mice. RNAseq analysis identified that E. coli-instilled WT mice expressed more inflammatory and fibrotic marker RNAs, such as Col3a1, Il1b, MMP3, Mmp7 and Cxcl12 than OPN-KO mice. CONCLUSIONS: Our results show that by preventing the inflammation-related increase in OPN levels, mice undergo accelerated recovery from fibrosis and do not develop chronic inflammation. This suggests that drugs targeting OPN signaling could be beneficial for LUTS patients whose symptoms are primarily linked to fibrosis. Source of Funding: The study was supported by an NIH NIDDK K01 (K01DK127150) and a K12 award (K12DK100022-06, both to PP) and by U54 DK104310 (to WAR and CMV) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e198-e199 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Petra Popovics More articles by this author Asha Jain More articles by this author Francesca Van More articles by this author Hannah Ruetten More articles by this author Mark Cadena More articles by this author Kristen S. Uchtmann More articles by this author Chad M. Vezina More articles by this author William A. Ricke More articles by this author Expand All Advertisement Loading ...