The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression

Mediators of Inflammation, Jan 2017

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo−/− mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4

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The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression

The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression Yu-Lei Gao, Bin Lu, Jian-Hua Zhai, Yan-Cun Liu, Hai-Xia Qi, Ying Yao, Yan-Fen Chai, and Song-Tao Shou Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China Correspondence should be addressed to Yu-Lei Gao; moc.621@828ieluyoag and Song-Tao Shou; moc.anis@66uohsts Received 11 October 2016; Revised 21 December 2016; Accepted 27 December 2016; Published 22 January 2017 Academic Editor: Mirella Giovarelli Copyright © 2017 Yu-Lei Gao et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo−/− mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25− T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo−/− mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor-β (), and the secretion of inhibitory cytokines [including TGF-β and interleukin- (IL-) 10], as well as CD4+ T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo−/− septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression. 1. Introduction Sepsis, which is defined as the life-threatening organ dysfunction caused by the dysregulated host response to infection, is the leading cause of MODS and death among critically ill patients [1–4]. There was a significant loss of immunocytes, mainly including B/T-lymphocytes and gastrointestinal epithelial cells, even at the beginning of sepsis [5–8]. It has been noted that patients gradually enter into a state of immunosuppression after primary hyperinflammatory response, especially cellular immunosuppression, defined as immunoparalysis, which could be a significant cause of the exacerbation of MODS or even death out of sepsis [2, 4]. More and more researches showed that modulating the immunosuppressive stage might be a promising interventional strategy to improve the outcome of sepsis [9]. With sepsis, Tregs subdued the process of inflammation and tissue damage while also causing immune dysfunction, including induction of T-lymphocytic apoptosis, inhibition of CD4+/CD8+ T-lymphocytic function, and mediation of shifting from the helper T cell (Th) 1 to Th 2 response via the expression of CTLA-4 and , as well as anti-inflammatory cytokines (IL-10 and TGF-β) [10–15]. Vit C, characterized as essential endogenous trace element and important physiological antioxidant, is involved in the incidence of sepsis and sepsis-induced MODS, even directly with the survival of septic patients [16, 17]. Vit C is identified as an essential component of the immunological response in humanity and experimental animals which augmented a variety of immune reaction, such as the development of mouse bone marrow derived progenitor cells to functional B/T-lymphocytes, the balance of Th1/Th2 response, and the increased serum levels of IgA and IgM, as well as regulating the balance of proliferation and apoptosis of T cells [18–21]. In addition, treatment with Vit C was correlated with the expression of Foxp-3, the demethylation of Foxp3-TSDR (Treg-specific demethylated region), and the suppressive capacity of Tregs in vitro [22]. Yet, direct effects of Vit C on sepsis-induced cellular immunosuppression are not known. Thus, further investigating the impact of Vit C on sepsis-induced cellular immunosuppression will provide a new evidence for understanding the mechanisms of Vit C in the treatment of sepsis. Humanity completely powerlessly synthesizes Vit C on account of the deficiency of L-gulono-γ-lactone oxidase (Gulo), which is the pivotal enzyme in the biosynthesis of Vit C; therefore we conducted studies in transgenic mice lacking Gulo 4 (Gulo−/−), to investigate the impact of parenteral Vit C on cellular immunosuppression in sepsis and sepsis-induced MODS. In the present stud (...truncated)


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Yu-Lei Gao, Bin Lu, Jian-Hua Zhai, Yan-Cun Liu, Hai-Xia Qi, Ying Yao, Yan-Fen Chai, Song-Tao Shou. The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression, Mediators of Inflammation, 2017, 2017, DOI: 10.1155/2017/4024672