110 NGF SIGNALING MEDIATES INFLAMMATORY CELL RESPONSES OF BLADDER TO THE INTRAVESICAL INSULTS

Abstract

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research (II)1 Apr 2013110 NGF SIGNALING MEDIATES INFLAMMATORY CELL RESPONSES OF BLADDER TO THE INTRAVESICAL INSULTS Mahendra Kashyap, Naoki Kawamorita, Michael Chancellor, Naoki Yoshimura, and Pradeep Tyagi Mahendra KashyapMahendra Kashyap Pittsburgh, PA More articles by this author , Naoki KawamoritaNaoki Kawamorita Pittsburgh, PA More articles by this author , Michael ChancellorMichael Chancellor Royal Oak, MI More articles by this author , Naoki YoshimuraNaoki Yoshimura Pittsburgh, PA More articles by this author , and Pradeep TyagiPradeep Tyagi Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1489AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Animals with bladder overactivity induced by intravesical insults such as acetic acid (AA) are an established model for OAB. Evidence for the role of NGF in OAB is mounting owing to rapid expression of NGF in response to bladder insults and the elevation of NGF and chemokines such as MCP-1, CXCL-1, and CXCL-10 in the urine of OAB patients reported by our group. The present work tested the hypothesis that increased bladder tissue levels of NGF drive the overexpression of inflammatory mediators following bladder exposure to AA. METHODS Adult female Sprague-Dawley rats were either exposed to intravesical infusion of saline or saline containing 0.25% acetic acid at the rate of 0.04ml/min for 3h under urethane anesthesia. Rats exposed to acetic acid were instilled 24h earlier for 30 min with vehicle (sham), NGF antisense or scrambled sequence oligonucleotides (ODN) complexed with liposomes. Rat bladders harvested at the end of AA infusion were analyzed for expression of NGF, chemokines, cytokines and adhesion molecules by Luminex xMAP analysis. RESULTS Intravesical AA infusion upregulated the expression of NGF, VEGF, MCP-1, leptin, CXCL-1, CXCL-10, ICAM-1 and E-selectin in the urothelium obtained from sham rats relative to the control group without acetic acid treatment ( p<0.05; ANOVA). NGF and other effectors were elevated in group pretreated with scrambled ODN (p<0.01). However, Sequence specific downregulation with NGF-antisense ODN-liposome complex blunted the expression of NGF and the downstream mediators such as. NGF levels irrespective of group +vely associated with VEGF (r=0.75,p<0.001) and -ively associated with ICAM-1 levels (rs = -0.5, p<0.01, whereas in scrambled group, levels of MCP-1 +vely correlated with NGF (r=0.88, p<0.01) (fig attached). CONCLUSIONS Reduced expression of chemokines accompanying NGF antisense supports the role of NGF as a key mediator responsible for bladder response to chemical stimuli. Expression of adhesion molecules ICAM-1 and E-selectin is prerequisite for the rolling and stable arrest of monocytes, neutrophils, lymphocytes chemoattracted by MCP-1, CXCL-1 and CXCL-10, respectively following AA exposure. Thus, local suppression of NGF in the bladder could be an attractive approach for the treatment OAB, which is often associated with chemokine/cytokine production in the bladder. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e44-e45 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Mahendra Kashyap Pittsburgh, PA More articles by this author Naoki Kawamorita Pittsburgh, PA More articles by this author Michael Chancellor Royal Oak, MI More articles by this author Naoki Yoshimura Pittsburgh, PA More articles by this author Pradeep Tyagi Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...