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      Defective Neutrophil Function in Patients with Sepsis Is Mostly Restored by ex vivo Ascorbate Incubation

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          Abstract

          Background

          Neutrophil function is essential for effective defence against bacterial infections but is defective in patients with sepsis. Ascorbate or vitamin C, which is low in the plasma of patients with sepsis, is stored inside human neutrophils and is essential for their normal function.

          Objective

          This study aimed to determine if ascorbate treatment ex vivo improved neutrophil function in patients with sepsis.

          Patients and Methods

          Human blood neutrophils were isolated from 20 patients with sepsis and 20 healthy age-matched controls. Neutrophils were incubated with or without ascorbate (1, 5, 10, 20 and 40 mM) for periods up to 2h. Chemotaxis was evaluated using a chemotactic chamber in response to the chemoattractant, fMLP. Phagocytosis (uptake of pHrodo red stained S. aureus) and apoptosis (annexin-V/propidium iodide staining) were measured by flow cytometry. Neutrophil extracellular trap (NET) formation was detected and quantified using DAPI, anti-myeloperoxidase and anti-neutrophil elastase immuno-fluorescence staining. Quantifluor detected the amount of dsDNA in NET supernatants, while quantitative PCR identified changes in expression of PADI4 gene.

          Results

          Chemotactic and phagocytic activities were decreased in patients with sepsis but increased after treatment with the high concentrations of ascorbate. Apoptosis was increased in the sepsis patients but not altered by ascorbate treatment. Spontaneous NET formation was observed in patients with sepsis. A quantity of 1mM ascorbate decreased spontaneous NETosis to that of normal, healthy neutrophils, while high concentrations of ascorbate (>10mM) further promoted NET formation.

          Conclusion

          Dysregulated neutrophil function was observed in patients with sepsis which could contribute to disease pathology and outcomes. Exposure to ascorbate could reverse some of these changes in function. These novel discoveries raise the possibility that ascorbate treatment could be used as an adjunctive therapy that could result in improved neutrophil function during sepsis.

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          Most cited references40

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          Sepsis definitions: time for change.

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            Sepsis: The evolution in definition, pathophysiology, and management

            There has been a significant evolution in the definition and management of sepsis over the last three decades. This is driven in part due to the advances made in our understanding of its pathophysiology. There is evidence to show that the manifestations of sepsis can no longer be attributed only to the infectious agent and the immune response it engenders, but also to significant alterations in coagulation, immunosuppression, and organ dysfunction. A revolutionary change in the way we manage sepsis has been the adoption of early goal-directed therapy. This involves the early identification of at-risk patients and prompt treatment with antibiotics, hemodynamic optimization, and appropriate supportive care. This has contributed significantly to the overall improved outcomes with sepsis. Investigation into clinically relevant biomarkers of sepsis are ongoing and have yet to yield effective results. Scoring systems such as the sequential organ failure assessment and Acute Physiology and Chronic Health Evaluation help risk-stratify patients with sepsis. Advances in precision medicine techniques and the development of targeted therapy directed at limiting the excesses of the inflammatory and coagulatory cascades offer potentially viable avenues for future research. This review summarizes the progress made in the diagnosis and management of sepsis over the past two decades and examines promising avenues for future research.
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              Neutrophil dysregulation during sepsis: an overview and update

              Abstract Sepsis remains a leading cause of death worldwide, despite advances in critical care, and understanding of the pathophysiology and treatment strategies. No specific therapy or drugs are available for sepsis. Neutrophils play a critical role in controlling infection under normal conditions, and it is suggested that their migration and antimicrobial activity are impaired during sepsis which contribute to the dysregulation of immune responses. Recent studies further demonstrated that interruption or reversal of the impaired migration and antimicrobial function of neutrophils improves the outcome of sepsis in animal models. In this review, we provide an overview of the associated mediators and signal pathways involved which govern the survival, migration and antimicrobial function of neutrophils in sepsis, and discuss the potential of neutrophils as a target to specifically diagnose and/or predict the outcome of sepsis.
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                Author and article information

                Journal
                J Inflamm Res
                J Inflamm Res
                JIR
                jinres
                Journal of Inflammation Research
                Dove
                1178-7031
                25 June 2020
                2020
                : 13
                : 263-274
                Affiliations
                [1 ]Translational Research in Inflammation and Immunology Research Unit, Faculty of Medicine, Chulalongkorn University , Bangkok, Thailand
                [2 ]Excellence Center for Critical Care Nephrology, King Chulalongkorn Memorial Hospital, Thai Red Cross Society , Bangkok, Thailand
                [3 ]Institute of Ageing and Chronic Disease, University of Liverpool , Liverpool, UK
                [4 ]Institute of Integrative Biology, University of Liverpool , Liverpool, UK
                Author notes
                Correspondence: Direkrit Chiewchengchol Email cdirekrit@live.com
                Article
                252433
                10.2147/JIR.S252433
                7326689
                32636666
                f0e4aeab-d408-41b0-9f31-0f6f3c96ac50
                © 2020 Sae-khow et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 04 March 2020
                : 10 June 2020
                Page count
                Figures: 4, Tables: 1, References: 58, Pages: 12
                Categories
                Original Research

                Immunology
                ascorbate,neutrophils,sepsis
                Immunology
                ascorbate, neutrophils, sepsis

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