Attenuation of Sepsis-Induced Organ Injury in Mice by Vitamin C
Bernard J. Fisher MS
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDonatas Kraskauskas DVM
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorErika J. Martin MT
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDaniela Farkas BS
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorPuneet Puri MD
Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorH. Davis Massey MD
Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorMichael O. Idowu MD
Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDonald F. Brophy PharmD
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorNorbert F. Voelkel MD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorAlpha A. Fowler III MD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorCorresponding Author
Ramesh Natarajan PhD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Ramesh Natarajan, Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, P.O. Box 980050, Richmond, VA 23298-0050, USA. Email: [email protected].Search for more papers by this authorBernard J. Fisher MS
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDonatas Kraskauskas DVM
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorErika J. Martin MT
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDaniela Farkas BS
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorPuneet Puri MD
Division of Gastroenterology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorH. Davis Massey MD
Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorMichael O. Idowu MD
Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorDonald F. Brophy PharmD
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorNorbert F. Voelkel MD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorAlpha A. Fowler III MD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Search for more papers by this authorCorresponding Author
Ramesh Natarajan PhD
Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
Ramesh Natarajan, Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, P.O. Box 980050, Richmond, VA 23298-0050, USA. Email: [email protected].Search for more papers by this authorAbstract
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. Materials and 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.
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