MP20-04 DNA DAMAGE REPAIR GENES REGULATE BLADDER INFLAMMATION

Abstract

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Kidney & Bladder II1 Apr 2015MP20-04 DNA DAMAGE REPAIR GENES REGULATE BLADDER INFLAMMATION Christopher Dru, Subhash Haldar, and Neil Bhowmick Christopher DruChristopher Dru More articles by this author , Subhash HaldarSubhash Haldar More articles by this author , and Neil BhowmickNeil Bhowmick More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.976AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chemical cystitis is a prevalent and bothersome inflammatory bladder condition characterized by dysuria and associated with cyclophosphamide and radiation therapy. It can progress to life-threatening gross hematuria and ulceration. The bladder mounts a multi-factorial immune response involving various pro- and anti- inflammatory pathways to mediate acute and chronic inflammation. The goal of this project was to determine the mechanisms underlying detrusor smooth muscle responsiveness caused by cyclophosphamide and identify the role of nicotinamide, a nutraceutical well-known for its anti-inflammatory effects, in inflammation attenuation. METHODS Ovariectomized C57Bl/6 mice received daily intraperitoneal injections of nicotinamide or placebo followed by administration of cyclophosphamide to induce chemical cystitis. Additionally, mouse bladder fibroblasts were cultured in the presence or absence of nicotinamide before induction of inflammation with acrolein. Tissues and cells were collected to determine the degree of biochemical and histological inflammation as well as changes in gene expression and cell death. RESULTS All mice and cultured cells pre-treated with nicotinamide before administration of cyclophosphamide or acrolein demonstrated a histological and biochemical decrease in inflammation. Nicotinamide increased DNA damage repair gene expression of Neil-1, Parp-1, OGG-1, and RAD-50 to reduce inflammation. FACS analysis using markers for cellular apoptosis demonstrated higher levels of cell survival (74% v 17%) when nicotinamide was added to cell-culture media before addition of acrolein. CONCLUSIONS Nicotinamide is an important regulator of inflammation and prevention of cell death in both mice treated with cyclophosphamide and cultured mouse bladder fibroblasts. This is evidenced by increased expression of DNA damage repair genes and alterations in cytokine regulation to protect the urothelium from reactive hyperplasia and ulceration. We propose that nicotinamide reduces inflammation through preservation of DNA integrity by maintaining physiologic levels of the DNA damage repair genes Neil-1, Parp-1, OGG-1, and RAD-50. These findings have future implications for the treatment of chemotherapy-induced cystitis as well as in the treatment of other types of inflammation. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e224 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Dru More articles by this author Subhash Haldar More articles by this author Neil Bhowmick More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...