Timing of developmental reduction in epithelial glutathione redox potential is associated with increased epithelial proliferation in the immature murine intestine

• Type of Material: Article
• Authors: Graham K. Reid, Emory University; Andrew J. Berardinelli, Emory University; Laurie Ray, Emory University; Arena R. Jackson, Emory University; Andrew Neish, Emory University; Jason Hansen, Emory University; Patricia Denning, Emory University
• Language: English
• Date: 2017-08-01
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option A
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 International Pediatric Research Foundation, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/pr.2017.49
• Title of Journal or Parent Work: Pediatric Research
• ISSN: 0031-3998
• Volume: 82
• Issue: 2
• Start Page: 362
• End Page: 369
• Grant/Funding Information: This work was supported by National Institutes of Health Grants DK076613 and HD059122 (P.W.D.), AI051282 and DK071604 (A.S.N.), and the Emory Digestive Diseases Research Center Grant R24 DK064399.
• Keywords: TISSUES; Science & Technology; CACO-2 CELLS; ANTIOXIDANTS; COUPLE; LOW-BIRTH-WEIGHT; NECROTIZING ENTEROCOLITIS; Life Sciences & Biomedicine; THIOL/DISULFIDE REDOX; Pediatrics; GLUTAMINE; INFANTS; STATE
• Research Categories: Health Sciences, Pathology; Biology, General

Abstract

Background The intracellular redox potential of the glutathione (GSH)/glutathione disulfide (GSSG) couple regulates cellular processes. In vitro studies indicate that a reduced GSH/GSSG redox potential favors proliferation, whereas a more oxidized redox potential favors differentiation. Intestinal growth depends upon an appropriate balance between the two. However, how the ontogeny of intestinal epithelial cellular (IEC) GSH/GSSG redox regulates these processes in the developing intestine has not been fully characterized in vivo.MethodsOntogeny of intestinal GSH redox potential and growth were measured in neonatal mice.ResultsWe show that IEC GSH/GSSG redox potential becomes increasingly reduced (primarily driven by increased GSH concentration) over the first 3 weeks of life. Increased intracellular GSH has been shown to drive proliferation through increased poly-ADP-ribose polymerase (PARP) activity. We show that increasing IEC poly-ADP-ribose chains can be measured over the first 3 weeks of life, indicating an increase in IEC PARP activity. These changes are accompanied by increased intestinal growth and IEC proliferation as assessed by villus height/crypt depth, intestinal length, and Ki67 staining.ConclusionUnderstanding how IEC GSH/GSSG redox potential is developmentally regulated may provide insight into how premature human intestinal redox states can be manipulated to optimize intestinal growth and adaptation.