Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury*

Fisher, Bernard; Seropián, Ignacio M.; Kraskauskas, Donatas; Thakkar, Jay N.; Voelkel, Norbert F.; Fowler, Alpha A.; Natarajan, Ramesh

doi:10.1097/ccm.0b013e3182120cb8

Cited by 165 publications

(169 citation statements)

References 41 publications

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“…Also, bolus injection of ascorbate or DHAA (200 mg/kg) decreases the concentration of protein in bronchoalveolar lavage fluid of LPS-exposed mice (17). Prevention by vitamin C of LPSinduced endothelial barrier dysfunction is a likely explanation for these findings.…”

Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 74%

“…Injection of DHAA (i.e., the oxidized state of vitamin C that cells take up and reduce to ascorbate) (200 mg/kg) also prolongs survival in FIP mice (18). Similarly, injection of ascorbate or DHAA (200 mg/kg) increases survival in mice made endotoxemic by exposure to LPS (17).…”

Section: Mortality and Morbiditymentioning

confidence: 99%

“…Histological analysis of the lungs shows extensive microvascular thrombosis in endotoxemic mice, except those treated with ascorbate or DHAA (17). Ascorbate and DHAA also blunt the induction by LPS of tissue factor mRNA in lung tissue, although whether they change the concentration of tissue factor protein at potential sites of blood clotting is unknown (17).…”

Section: Coagulopathy and Capillary Pluggingmentioning

confidence: 99%

“…Similarly, when mice are made endotoxemic by injection of LPS, blood samples obtained from them by cardiac puncture show prolonged prothrombin times and activated partial thromboplastin times (17). Ascorbate (200 mg/kg) or DHAA (200 mg/kg) injection mitigates this LPS-induced hypocoagulability in systemic blood (17).…”

Section: Coagulopathy and Capillary Pluggingmentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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Significance: Evidence is emerging that parenteral administration of high-dose vitamin C may warrant development as an adjuvant therapy for patients with sepsis. Recent Advances: Sepsis increases risk of death and disability, but its treatment consists only of supportive therapies because no specific therapy is available. The characteristics of severe sepsis include ascorbate (reduced vitamin C) depletion, excessive protein nitration in microvascular endothelial cells, and microvascular dysfunction composed of refractive vasodilation, endothelial barrier dysfunction, and disseminated intravascular coagulation. Parenteral administration of ascorbate prevents or even reverses these pathological changes and thereby decreases hypotension, edema, multiorgan failure, and death in animal models of sepsis. Critical Issues: Dehydroascorbic acid appears to be as effective as ascorbate for protection against microvascular dysfunction, organ failure, and death when injected in sepsis models, but information about pharmacodynamics and safety in human subjects is only available for ascorbate. Although the plasma ascorbate concentration in critically ill and septic patients is normalized by repletion protocols that use high doses of parenteral ascorbate, and such doses are tolerated well by most healthy subjects, whether such large amounts of the vitamin trigger adverse effects in patients is uncertain. Future Directions: Further study of sepsis models may determine if high concentrations of ascorbate in interstitial fluid have pro-oxidant and bacteriostatic actions that also modify disease progression. However, the ascorbate depletion observed in septic patients receiving standard care and the therapeutic mechanisms established in models are sufficient evidence to support clinical trials of parenteral ascorbate as an adjuvant therapy for sepsis.

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Section: Extravasation Of Plasma Proteins and Fluidmentioning

confidence: 74%

Section: Mortality and Morbiditymentioning

confidence: 99%

Section: Coagulopathy and Capillary Pluggingmentioning

confidence: 99%

Section: Coagulopathy and Capillary Pluggingmentioning

confidence: 99%

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Evaluation of Vitamin C for Adjuvant Sepsis Therapy

Wilson

2013

Antioxidants & Redox Signaling

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“…In our pre-clinical studies, we showed that parenteral infusion of ascorbic acid (200 mg/kg) could attenuate sepsis induced organ injury in wild type mice [2,3] and in vitamin C knockout mice (lacking L-gulono-γ-lactone oxidase, Gulo) [4]. In these studies parenteral ascorbic acid was effective at reducing mortality and sepsis-induced organ injury through pleiotropic mechanisms including down-regulation of pro-inflammatory mediator secretion, normalization of coagulopathy, improved alveolar fluid clearance and enhanced alveolar epithelial barrier function.…”

Section: Introductionmentioning

confidence: 99%

Impact of Intravenous Ascorbic Acid Infusion on Novel Biomarkers in Patients with Severe Sepsis

Natarajan¹

2014

J Pulm Respir Med

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Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis.Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured.Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups. Conclusion:Ascorbic acid infusion may improve sepsis outcomes by reducing cf-and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.

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