Ex Vivo Evaluation of the Sepsis Triple Therapy High-Dose Vitamin C in Combination with Vitamin B1 and Hydrocortisone in a Human Peripheral Blood Mononuclear Cells (PBMCs) Model

Abstract

Sepsis is an extremely complex clinical syndrome, usually involving an excessive inflammatory response including an overshooting cytokine release that damages tissue and organs of the patient. Due to the severity of this condition, it is estimated that over 11 million people die from sepsis each year. Despite intensive research in the field, there is still no specific therapy for sepsis. Many sepsis patients show a marked deficiency of vitamin C. 9 out of 10 sepsis patients have a hypovitaminosis C, and every third patient even shows a clinical deficiency in the scurvy range. In addition, low vitamin C levels of intensive care sepsis patients correlate with a higher need for vasopressors, higher Sequential Organ Failure Assessment (SOFA) scores, and increased mortality. Based on this observation and the conducted clinical trials using vitamin C as sepsis therapy in intensive care patients, the aim of the present ex vivo study was to evaluate the effects of high-dose vitamin C alone and in a triple combination supplemented with vitamin B1 (thiamine) and hydrocortisone on the lipopolysaccharide (LPS)-induced cytokine response in peripheral blood mononuclear cells (PBMCs) from healthy human donors. We found that all corticosteroid combinations strongly reduced the cytokine response on RNA- and protein levels, while high-dose vitamin C alone significantly diminished the PBMC mediated secretion of the cytokines interleukin (IL)-10, IL-23, and monocyte chemo-attractant protein (MCP-1), which mediate the inflammatory response. However, vitamin C showed no enhancing effect on the secretion of further cytokines studied. This data provides important insights into the possible immunomodulatory function of vitamin C in an ex vivo setting of human PBMCs and the modulation of their cytokine profile in the context of sepsis. Since vitamin C is a vital micronutrient, the restoration of physiologically adequate concentrations should be integrated into routine sepsis therapy, and the therapeutic effects of supraphysiological concentrations of vitamin C in sepsis patients should be further investigated in clinical trials.

Effect of Anti-Inflammatory and Antimicrobial Cosupplementations on Sepsis Prevention in Critically Ill Trauma Patients at High Risk for Sepsis

“…Lactobacillus delbrueckii is one of the two probiotic strain constituents of the probiotic product used in this study ( Lacteol Forte [package insert], 2018 ). The results of the ex vivo study of Lauer et al (2021) support the findings of the significantly reduced MCP-1 level on day 6 within the HR-CB group. The average steady-state serum vitamin C concentration in the HR-CB group [0.4 mM, estimated based on dosing rate (1 g every 12 h), salt value (0.889), and clearance (0.92 L/h)] is within the range of vitamin C concentration as investigated in the Lauer et al study (0.2–2 mM) ( Lauer et al, 2021 ).…”

“…Differently from this study, previous studies investigating the effects of interventions (CB and DP) on MCP-1 levels were either preclinical or clinical on patients without trauma (Dong et al, 2011;Alvarez et al, 2013;Lauer et al, 2021). The significantly reduced incidence of sepsis development by the end of the first week in both the HR-DP and HR-CB groups compared to the HR-C group was accompanied by a significant reduction in the proinflammatory chemokine MCP-1 level within these intervention groups compared to a significant increase within the control group.…”

Engineered Extracellular Vesicles Derived from Dermal Fibroblasts Attenuate Inflammation in a Murine Model of Acute Lung Injury

“…Ascorbic acid (vitamin C) is a potent antioxidant that has been reported to provide protection against reactive oxygen species, preventing the damaging effects of oxidative stress, and it is also known for its anti-inflammatory role. [104,105] Previous studies have shown that ascorbic acid attenuates systemic inflammation induced by acute lung injury. [106] Likewise, oxoglutarate has been reported to have antioxidant properties and to play a key role in macrophage polarization into an M2 anti-inflammatory phenotype.…”

Ex vivo and in vitro Monocyte Responses Do Not Reflect in vivo Immune Responses and Tolerance

“…In this context, a low EV cytokine response is presumed to reflect a suppressed in vivo (IV) "immune status" and has therefore frequently been proposed as a diagnostic tool to identify patients who might benefit from immunostimulatory therapy [13][14][15]. Furthermore, EV and in vitro stimulations of leukocytes are widely applied techniques in translational studies to investigate immunophysiological mechanisms or to test potential therapeutic interventions [16][17][18]. However, surprisingly little is known about whether these EV and in vitro models adequately reflect the IV situation.…”