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      The Emerging Role of Vitamin C as a Treatment for Sepsis

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          Abstract

          Sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection, is a leading cause of morbidity and mortality worldwide. Decades of research have failed to identify any specific therapeutic targets outside of antibiotics, infectious source elimination, and supportive care. More recently, vitamin C has emerged as a potential therapeutic agent to treat sepsis. Vitamin C has been shown to be deficient in septic patients and the administration of high dose intravenous as opposed to oral vitamin C leads to markedly improved and elevated serum levels. Its physiologic role in sepsis includes attenuating oxidative stress and inflammation, improving vasopressor synthesis, enhancing immune cell function, improving endovascular function, and epigenetic immunologic modifications. Multiple clinical trials have demonstrated the safety of vitamin C and two recent studies have shown promising data on mortality improvement. Currently, larger randomized controlled studies are underway to validate these findings. With further study, vitamin C may become standard of care for the treatment of sepsis, but given its safety profile, current treatment can be justified with compassionate use.

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          Most cited references95

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          Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones

          Neutrophils play an important role in innate immunity by defending the host organism against invading microorganisms. Antimicrobial activity of neutrophils is mediated by release of antimicrobial peptides, phagocytosis as well as formation of neutrophil extracellular traps (NET). These structures are composed of DNA, histones and granular proteins such as neutrophil elastase and myeloperoxidase. This study focused on the influence of NET on the host cell functions, particularly on human alveolar epithelial cells as the major cells responsible for gas exchange in the lung. Upon direct interaction with epithelial and endothelial cells, NET induced cytotoxic effects in a dose-dependent manner, and digestion of DNA in NET did not change NET-mediated cytotoxicity. Pre-incubation of NET with antibodies against histones, with polysialic acid or with myeloperoxidase inhibitor but not with elastase inhibitor reduced NET-mediated cytotoxicity, suggesting that histones and myeloperoxidase are responsible for NET-mediated cytotoxicity. Although activated protein C (APC) did decrease the histone-induced cytotoxicity in a purified system, it did not change NET-induced cytotoxicity, indicating that histone-dependent cytotoxicity of NET is protected against APC degradation. Moreover, in LPS-induced acute lung injury mouse model, NET formation was documented in the lung tissue as well as in the bronchoalveolar lavage fluid. These data reveal the important role of protein components in NET, particularly histones, which may lead to host cell cytotoxicity and may be involved in lung tissue destruction.
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            Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death.

            Neutrophil interaction with activated endothelial cells (EC) is required for transmigration. We examined consequences of this interaction on NETosis. Co-culture of activated EC with neutrophils induced neutrophil extracellular trap (NET) formation, which was partially dependent on production of IL-8 by activated EC. Extended neutophil/EC co-culture resulted in EC damage, which could be abrogated by inclusion of either diphenyleneiodonium to inhibit the NAPDH oxidase pathway required for NETosis, or DNAse to disrupt NETs. These findings offer new insight into mechanisms whereby NETs trigger damage to the endothelium in sepsis, small vessel vasculitis and possibly the villous trophoblast in preeclampsia. Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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              Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury

              Neutrophils dominate the early immune response in pathogen-induced acute lung injury, but efforts to harness their responses have not led to therapeutic advancements. Neutrophil extracellular traps (NETs) have been proposed as an innate defense mechanism responsible for pathogen clearance, but there are concerns that NETs may induce collateral damage to host tissues. Here, we detected NETs in abundance in mouse models of severe bacterial pneumonia/acute lung injury and in human subjects with acute respiratory distress syndrome (ARDS) from pneumonia or sepsis. Decreasing NETs reduced lung injury and improved survival after DNase I treatment or with partial protein arginine deiminase 4 deficiency ( PAD4 +/– ). Complete PAD4 deficiency ( PAD4 –/– ) reduced NETs and lung injury but was counterbalanced by increased bacterial load and inflammation. Importantly, we discovered that the lipoxin pathway could be a potent modulator of NET formation, and that mice deficient in the lipoxin receptor ( Fpr2 –/– ) produced excess NETs leading to increased lung injury and mortality. Lastly, we observed in humans that increased plasma NETs were associated with ARDS severity and mortality, and lower plasma DNase I levels were associated with the development of sepsis-induced ARDS. We conclude that a critical balance of NETs is necessary to prevent lung injury and to maintain microbial control, which has important therapeutic implications. Neutrophil extracellular traps (NETs) are released after bacterial pneumonia in mice and in humans with acute respiratory distress syndrome, and contribute to lung barrier disruption.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                22 January 2020
                February 2020
                : 12
                : 2
                : 292
                Affiliations
                [1 ]Department of Internal Medicine, Division of Pulmonary Disease and Critical Care Medicine, Virginia Commonwealth University School of Medicine, 1200 E Broad St., P.O. Box 980050, Richmond, VA 23298, USA; michael.lheureux@ 123456vcuhealth.org (M.L.); casey.cable@ 123456vcuhealth.org (C.A.C.); bernard.fisher@ 123456vcuhealth.org (B.J.F.); alpha.fowler@ 123456vcuhealth.org (A.A.F.)
                [2 ]Department of Surgery, Division of Acute Care Surgical Services, Virginia Commonwealth University School of Medicine, 1200 E Broad St., P.O. Box 980454, Richmond, VA 23298, USA; stefan.leichtle@ 123456vcuhealth.org
                Author notes
                [* ]Correspondence: markos.kashiouris@ 123456vcuhealth.org ; Tel.: +1-(804)-828-9893
                Author information
                https://orcid.org/0000-0001-5184-3030
                https://orcid.org/0000-0003-2670-8907
                https://orcid.org/0000-0002-6774-0682
                Article
                nutrients-12-00292
                10.3390/nu12020292
                7070236
                31978969
                e22c0893-45bd-4bb9-ba2a-dc513f8c9924
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 December 2019
                : 16 January 2020
                Categories
                Review

                Nutrition & Dietetics
                vitamin c,high-dose intravenous vitamin c,hdivc,sepsis,septic shock
                Nutrition & Dietetics
                vitamin c, high-dose intravenous vitamin c, hdivc, sepsis, septic shock

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