title: Attenuation of sepsis-induced organ injury in mice by vitamin C.
abstract: BACKGROUND
  Multiple organ dysfunction syndrome (MODS) is the principal cause of death in patients with sepsis. Recent work supports the notion that parenteral vitamin C (VitC) is protective in sepsis through pleiotropic mechanisms. Whether suboptimal levels of circulating VitC increase susceptibility to sepsis-induced MODS is unknown.
  
  
  METHODS
  Unlike mice, humans lack the ability to synthesize VitC because of loss of L-gulono-γ-lactone oxidase (Gulo), the final enzyme in the biosynthesis of VitC. To examine whether physiological levels of VitC are required for defense against a catastrophic infection, we induced sepsis in VitC sufficient and VitC deficient Gulo(-/-) mice by intraperitoneal infusion of a fecal stem solution (FIP). Some VitC deficient Gulo(-/-) mice received a parenteral infusion of ascorbic acid (AscA, 200 mg/kg) 30 minutes after induction of FIP. We used molecular, histological, and biochemical analyses to assess for MODS as well as abnormalities in the coagulation system and circulating blood cells.
  
  
  RESULTS
  FIP produced injury to lungs, kidneys and liver (MODS) in VitC deficient Gulo(-/-) mice. MODS was not evident in FIP-exposed VitC sufficient Gulo(-/-) mice and attenuated in VitC deficient Gulo(-/-) mice infused with AscA. Septic VitC deficient Gulo(-/-) mice developed significant abnormalities in the coagulation system and circulating blood cells. These were attenuated by VitC sufficiency/infusion in septic Gulo(-/-) mice.
  
  
  CONCLUSIONS
  VitC deficient Gulo(-/-) mice were more susceptible to sepsis-induced MODS. VitC sufficiency or parenteral infusion of VitC, following induction of sepsis, normalized physiological functions that attenuated the development of MODS in sepsis.
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Fisher
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Martin
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.affiliation: Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Puneet
authors.initials: P
authors.lastname: Puri
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: H Davis
authors.initials: HD
authors.lastname: Massey
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Idowu
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Brophy
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Alpha A
authors.initials: AA
authors.lastname: Fowler
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA rnataraj@vcu.edu.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D001206:Ascorbic Acid Deficiency / Q000150:complications / Q000628:therapy*; D001773:Blood Cells; D001777:Blood Coagulation; D007263:Infusions, Parenteral; D007668:Kidney; D050544:L-Gulonolactone Oxidase / Q000172:deficiency / Q000378:metabolism; D008099:Liver; D008168:Lung; D018345:Mice, Knockout; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D018805:Sepsis / Q000150:complications*; D014815:Vitamins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014815:Vitamins; D050544:L-Gulonolactone Oxidase; D001205:Ascorbic Acid
keywords: L-gulono-γ-lactone oxidase; coagulation; inflammation; multiple organ dysfunction syndrome; sepsis; vitamin C