title: Resolution of sterile inflammation: role for vitamin C.
abstract: BACKGROUND
  Macrophage reprogramming is vital for resolution of acute inflammation. Parenteral vitamin C (VitC) attenuates proinflammatory states in murine and human sepsis. However information about the mechanism by which VitC regulates resolution of inflammation is limited.
  
  
  METHODS
  To examine whether physiological levels of VitC modulate resolution of inflammation, we used transgenic mice lacking L-gulono-γ-lactone oxidase. VitC sufficient/deficient mice were subjected to a thioglycollate-elicited peritonitis model of sterile inflammation. Some VitC deficient mice received daily parenteral VitC (200 mg/kg) for 3 or 5 days following thioglycollate infusion. Peritoneal macrophages harvested on day 3 or day 5 were examined for intracellular VitC levels, pro- and anti-inflammatory protein and lipid mediators, mitochondrial function, and response to lipopolysaccharide (LPS). The THP-1 cell line was used to determine the modulatory activities of VitC in activated human macrophages.
  
  
  RESULTS
  VitC deficiency significantly delayed resolution of inflammation and generated an exaggerated proinflammatory response to in vitro LPS stimulation. VitC sufficiency and in vivo VitC supplementation restored macrophage phenotype and function in VitC deficient mice. VitC loading of THP-1 macrophages attenuated LPS-induced proinflammatory responses.
  
  
  CONCLUSIONS
  VitC sufficiency favorably modulates macrophage function. In vivo or in vitro VitC supplementation restores macrophage phenotype and function leading to timely resolution of inflammation.
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA 23298-0533, USA ; Department of Clinical Pharmacy, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
authors.forename: Bassem M
authors.initials: BM
authors.lastname: Mohammed
authors.affiliation: Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University, P.O. Box 980050, Richmond, VA 23298-0050, USA.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Fisher
authors.affiliation: Department of Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Quoc K
authors.initials: QK
authors.lastname: Huynh
authors.affiliation: Research Service, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249, USA ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Dayanjan S
authors.initials: DS
authors.lastname: Wijesinghe
authors.affiliation: Research Service, Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, VA 23249, USA ; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA ; The Massey Cancer Center, Richmond, VA 23298, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Chalfant
authors.affiliation: Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA 23298-0533, 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, P.O. Box 980050, Richmond, VA 23298-0050, 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, P.O. Box 980050, Richmond, VA 23298-0050, USA.
authors.forename: Ramesh
authors.identifier: 0000-0002-3431-9971
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism* / Q000627:therapeutic use*; D015153:Blotting, Western; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D013864:Thioglycolates / Q000633:toxicity
chemical_list: D008070:Lipopolysaccharides; D013864:Thioglycolates; D001205:Ascorbic Acid