title: Shifting anaerobic to aerobic metabolism stimulates apoptosis through modulation of redox balance: potential intervention in the pathogenesis of postoperative adhesions.
abstract: OBJECTIVE
  To compare the effect of shifting anaerobic to aerobic metabolism on key regulators of oxidative stress, including extracellular superoxide dismutase (SOD3), inducible nitric oxide synthase (iNOS), and its product, nitric oxide (NO), as well as mitochondrial potential (Δψm) and apoptosis in fibroblasts established from normal peritoneum and adhesion tissues.
  
  
  METHODS
  Prospective, experimental study.
  
  
  METHODS
  University medical center.
  
  
  METHODS
  Fibroblasts established from normal peritoneum and adhesion tissues from the same patients.
  
  
  METHODS
  Treatment with dichloroacetate (0, 20, 40, and 80 μg/mL, 24 hours).
  
  
  METHODS
  The expression of SOD3, iNOS, and NO levels were measured utilizing real-time reverse transcription-polymerase chain reaction and Greiss assay. The Δψm was evaluated by the JC-1 Mitochondrial Membrane Potential Assay. Apoptosis was determined by caspase-3 activity and TUNEL assays. Data were analyzed using SPSS 19.0. Mixed model repeated-measures analysis of variance was used with a Bonferroni correction. Significant interactions were analyzed with independent sample t tests.
  
  
  RESULTS
  Dichloroacetate increased apoptosis, SOD3 messenger RNA, iNOS messenger RNA, and NO levels in fibroblasts from peritoneum and adhesions. There was enhanced Δψm adhesion as compared with normal peritoneal fibroblasts. Creating oxidative stress by exposure by hypoxia markedly increased Δψm in fibroblasts from normal peritoneum to levels observed in adhesions; dichloroacetate protected against the effects of hypoxia.
  
  
  CONCLUSIONS
  Anaerobic metabolism and oxidative stress are associated with the development of the adhesion phenotype, which manifests decreased apoptosis. Dichloroacetate induces adhesion fibroblasts to undergo apoptosis via modulation of redox homeostasis. These findings may provide targets for therapeutic treatment for reduction of profibrotic disorders, including postoperative adhesions.
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Fletcher
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Awoniyi O
authors.initials: AO
authors.lastname: Awonuga
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Bailey R
authors.initials: BR
authors.lastname: Neubauer
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Abusamaan
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Mohammed G
authors.initials: MG
authors.lastname: Saed
authors.affiliation: Department of Obstetrics and Gynecology, Georgia Regents University, Augusta, Georgia.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Diamond
authors.affiliation: Department of Obstetrics and Gynecology, The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, Michigan. Electronic address: gsaed@med.wayne.edu.
authors.forename: Ghassan M
authors.initials: GM
authors.lastname: Saed
mesh_terms: D000332:Aerobiosis / Q000502:physiology; D000693:Anaerobiosis / Q000502:physiology; D017209:Apoptosis / Q000235:genetics; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D010532:Peritoneal Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010537:Peritoneum / Q000378:metabolism / Q000473:pathology; D011183:Postoperative Complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000267:Tissue Adhesions / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: Dichloroacetate; apoptosis; oxidative stress; postoperative adhesions