title: Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis.
abstract: Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhoea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H2O2mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H2O2degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H2O. Mice were administered either pegylated catalase or saline at day -1, 0 and +1 of DSS treatment. Ion transport responses to the Ca2+-dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic Iscresponses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na+-K+-2Cl-cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhoea.
authors.affiliation: Division of Gastroenterology, University of California, San Diego School of Medicine, La Jolla, CA, USA.
authors.forename: Kim E
authors.initials: KE
authors.lastname: Barrett
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, USA. declan.mccole@ucr.edu.
authors.forename: Declan F
authors.initials: DF
authors.lastname: McCole
mesh_terms: D000818:Animals; D002374:Catalase / Q000494:pharmacology / Q000627:therapeutic use*; D003092:Colitis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017136:Ion Transport / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009924:Organ Culture Techniques
chemical_list: D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D002374:Catalase
keywords: ERK phosphorylation; NKCC1; chloride secretion; diarrhoea; epithelium; inflammation; mucosa; reactive oxygen species