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Cited by 59Vitamin C and Antioxidants ResearchSepsis Diagnosis and TreatmentNitric Oxide and Endothelin Effects

Vitamin C and Microvascular Dysfunction in Systemic Inflammation

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Tyml, Karel·2017·Antioxidants
DOI 10.3390/antiox6030049PMC PMC5618077
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Abstract

Sepsis, life-threatening organ dysfunction caused by a dysfunctional host response to infection, is associated with high mortality. A promising strategy to improve the outcome is to inject patients intravenously with ascorbate (vitamin C). In animal models of sepsis, this injection improves survival and, among others, the microvascular function. This review examines our recent work addressing ascorbate’s ability to inhibit arteriolar dysfunction and capillary plugging in sepsis. Arteriolar dysfunction includes impaired vasoconstriction/dilation (previously reviewed) and impaired conduction of vasoconstriction/dilation along the arteriole. We showed that ascorbate injected into septic mice prevents impaired conducted vasoconstriction by inhibiting neuronal nitric oxide synthase-derived NO, leading to restored inter-endothelial electrical coupling through connexin 37-containing gap junctions. Hypoxia/reoxygenation (confounding factor in sepsis) also impairs electrical coupling by protein kinase A (PKA)-dependent connexin 40 dephosphorylation; ascorbate restores PKA activation required for this coupling. Both effects of ascorbate could explain its ability to protect against hypotension in sepsis. Capillary plugging in sepsis involves P-selectin mediated platelet-endothelial adhesion and microthrombi formation. Early injection of ascorbate prevents capillary plugging by inhibiting platelet-endothelial adhesion and endothelial surface P-selectin expression. Ascorbate also prevents thrombin-induced platelet aggregation and platelet surface P-selectin expression, thus preventing microthrombi formation. Delayed ascorbate injection reverses capillary plugging and platelet-endothelial adhesion; it also attenuates sepsis-induced drop in platelet count in systemic blood. Thrombin-induced release of plasminogen-activator-inhibitor-1 from platelets (anti-fibrinolytic event in sepsis) is inhibited by ascorbate pH-dependently. Thus, under acidotic conditions in sepsis, ascorbate promotes dissolving of microthrombi in capillaries. We propose that protected/restored arteriolar conduction and capillary bed perfusion by ascorbate contributes to reduced organ injury and improved survival in sepsis.

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  • Circulating levels of copper, selenium, zinc, and vitamins E and C are decreased below reference ranges in severe critical care conditions in association with intense inflammation.

    “The antioxidant micronutrients, and in particular copper, selenium, zinc, and vitamins E and C belong to the primary antioxidant defenses: their circulating levels are decreased below reference ranges in these conditions (282,283,284,285) in association with intense inflammation.”

    From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [284]

    The Introduction reports that plasma vitamin C is depleted in septic elderly patients (about 10 μM, versus about 40 μM in healthy elderly people) and describes sepsis as a systemic inflammatory condition. It does not report decreased circulating copper, selenium, zinc, or vitamin E, or establish that all these nutrients fall below reference ranges across severe critical-care conditions. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Selenium supports the activity of the glutathione peroxidase family of antioxidant enzymes, while vitamin C primarily acts on the endothelium and microcirculation.

    “Regarding high dose intervention, selenium and vitamin C will be commented upon separately as their mechanisms of action differ: Se supports the activity of the glutathione peroxidase family of antioxidant enzymes, while vitamin C primarily acts on the endothelium and microcirculation (284, 289).”

    From ESPEN guideline on clinical nutrition in the intensive care unit. (2019) · cites this paper as [284]

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Authors
Tyml, K.
Affiliations
Western University (CA)
Corresponding author
Tyml, Karel
Venue
Antioxidants
Publisher
MDPI AG
Published
2017-06-29
Volume
6
Issue
3
Pages
49
ISSN
2076-3921 (ISSN-L)
DOI
10.3390/antiox6030049
PMC
PMC5618077
OpenAlex
W2731879171
Cited by
59
References
4
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 7 · 2022: 12 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 6
FWCI
0.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Heart and Stroke Foundation of Canada
  • Canadian Institutes of Health Research
Topics
  • Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Keywords
vitamin C, sepsis, microvascular dysfunction, neuronal nitric oxide synthase, nitric oxide, connexin 37, connexin 40, protein kinase A, hypoxia/reoxygenation, P-selectin, microthrombi, thrombin-induced platelet aggregation, plasminogen activator inhibitor-1, acidosis, hypotension, organ dysfunction

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