title: Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid.
abstract: Bacterial infections of the lungs and abdomen are among the most common causes of sepsis. Abdominal peritonitis often results in acute lung injury (ALI). Recent reports demonstrate a potential benefit of parenteral vitamin C [ascorbic acid (AscA)] in the pathogenesis of sepsis. Therefore we examined the mechanisms of vitamin C supplementation in the setting of abdominal peritonitis-mediated ALI. We hypothesized that vitamin C supplementation would protect lungs by restoring alveolar epithelial barrier integrity and preventing sepsis-associated coagulopathy. Male C57BL/6 mice were intraperitoneally injected with a fecal stem solution to induce abdominal peritonitis (FIP) 30 min prior to receiving either AscA (200 mg/kg) or dehydroascorbic acid (200 mg/kg). Variables examined included survival, extent of ALI, pulmonary inflammatory markers (myeloperoxidase, chemokines), bronchoalveolar epithelial permeability, alveolar fluid clearance, epithelial ion channel, and pump expression (aquaporin 5, cystic fibrosis transmembrane conductance regulator, epithelial sodium channel, and Na(+)-K(+)-ATPase), tight junction protein expression (claudins, occludins, zona occludens), cytoskeletal rearrangements (F-actin polymerization), and coagulation parameters (thromboelastography, pro- and anticoagulants, fibrinolysis mediators) of septic blood. FIP-mediated ALI was characterized by compromised lung epithelial permeability, reduced alveolar fluid clearance, pulmonary inflammation and neutrophil sequestration, coagulation abnormalities, and increased mortality. Parenteral vitamin C infusion protected mice from the deleterious consequences of sepsis by multiple mechanisms, including attenuation of the proinflammatory response, enhancement of epithelial barrier function, increasing alveolar fluid clearance, and prevention of sepsis-associated coagulation abnormalities. Parenteral vitamin C may potentially have a role in the management of sepsis and ALI associated with sepsis.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298-0050, USA.
authors.forename: Bernard J
authors.initials: BJ
authors.lastname: Fisher
authors.forename: Donatas
authors.initials: D
authors.lastname: Kraskauskas
authors.forename: Erika J
authors.initials: EJ
authors.lastname: Martin
authors.forename: Daniela
authors.initials: D
authors.lastname: Farkas
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Wegelin
authors.forename: Donald
authors.initials: D
authors.lastname: Brophy
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Ward
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Alpha A
authors.initials: AA
authors.lastname: Fowler
authors.forename: Ramesh
authors.initials: R
authors.lastname: Natarajan
mesh_terms: D000005:Abdomen / Q000382:microbiology / Q000473:pathology; D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D018893:Bronchoalveolar Lavage / Q000379:methods; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D007473:Ion Channels / Q000378:metabolism; D017136:Ion Transport / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010538:Peritonitis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology; D010539:Permeability / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D003598:Cytoskeletal Proteins; D007473:Ion Channels; D000254:Sodium-Potassium-Exchanging ATPase; D001205:Ascorbic Acid