title: Hydrogen peroxide modulates the proliferation/quiescence switch in the liver during embryonic development and posthepatectomy regeneration.
abstract: OBJECTIVE
  The liver undergoes marked changes in the rate of proliferation during normal development and regeneration through the coordinated activity of numerous signaling pathways. Little is known, however, about the events that act upstream of these signaling pathways. Here, we explore the modulatory effects of hydrogen peroxide (H2O2) on these pathways in the context of liver development and regeneration.
  
  
  RESULTS
  We show that H2O2 production during liver development and after partial hepatectomy is tightly regulated in time by specific H2O2-producing and scavenging proteins and dose dependently triggers two distinct pathways. Sustained elevated H2O2 levels are required for the activation of ERK signaling and trigger a shift from quiescence to proliferation. Contrastingly, sustained decreased H2O2 levels are required for the activation of p38 signaling and trigger a shift from proliferation to quiescence. Both events impact the cyclin D and Rb pathways and are involved in liver development and regeneration. Pharmacological lowering of H2O2 levels reduces the extent of fetal hepatocyte proliferation and delays the onset of liver regeneration. Chemical augmentation of H2O2 levels in adult hepatocytes triggers proliferation and delays the termination of liver regeneration.
  
  
  METHODS
  Our results challenge the traditional view of H2O2 as a deleterious stressor in response to liver damage and identify a novel role of endogenous H2O2 in liver development and regeneration.
  
  
  CONCLUSIONS
  Endogenous H2O2 production is tightly regulated during liver development and regeneration. H2O2 constitutes an important trigger for the proliferation and quiescence transition in hepatocytes via the concentration-dependent activation of the ERK or p38 pathway.
authors.affiliation: Department of Toxicology, Shaanxi Provincial Key Laboratory of Free Radical Biology and Medicine, The Ministry of Education Key Laboratory of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University , Xi'an, China .
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Xu-Jun
authors.initials: XJ
authors.lastname: Qin
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Jiang-Zheng
authors.initials: JZ
authors.lastname: Liu
authors.forename: Chun-Xu
authors.initials: CX
authors.lastname: Hai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D016877:Oxidants / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016877:Oxidants; D006861:Hydrogen Peroxide; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose