title: Timing of developmental reduction in epithelial glutathione redox potential is associated with increased epithelial proliferation in the immature murine intestine.
abstract: BackgroundThe 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.
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Graham K
authors.initials: GK
authors.lastname: Reid
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Berardinelli
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Laurie
authors.initials: L
authors.lastname: Ray
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Arena R
authors.initials: AR
authors.lastname: Jackson
authors.affiliation: Division of Epithelial Pathobiology, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Neish
authors.affiliation: Department of Physiology and Developmental Biology, College of Life Sciences, Brigham Young University, Provo, Utah.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Hansen
authors.affiliation: Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Denning
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011064:Poly Adenosine Diphosphate Ribose; D005978:Glutathione