Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium.

This paper by Dr John Wilson discusses the potential usefulness of using Vitamin C for the treatment of septic shock. As with most things serious, the earlier the treatment the better. The article is quite technical and complex, it is unfortunately for the reader a technical and complex problem.

If you are not familiar with this sort of research, or are struggling with some of the terms, we recommend that you read the Endotoxin and Vitamin C newsletter attached at the bottom of this column before you start on Dr Wilson's excellent paper.

Is there a take-home message about this? Of course! Vitamin C, in sufficient concentartion, blocks or interferes with most of the major pathological changes that occur in septic shock.

Read on...

Abstract

Circulating levels of vitamin C (ascorbate) are low in patients with sepsis. Parenteral administration of ascorbate raises plasma and tissue concentrations of the vitamin and may decrease morbidity. In animal models of sepsis, intravenous ascorbate injection increases survival and protects several microvascular functions, namely, capillary blood flow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators. The effects of parenteral ascorbate on microvascular function are both rapid and persistent. Ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox-sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase. These observations are consistent with the hypothesis that microvascular function in sepsis may be improved by parenteral administration of ascorbate as an adjuvant therapy.

Original study authors:
Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors. 2009 Jan-Feb;35(1):5-13. Review. PubMed PMID: 19319840; PubMed Central PMCID: PMC2767105

The full paper is available here.

Discussion:
"Subnormal ascorbate concentrations in plasma and leukocytes are common features of the critically ill in general and of patients with sepsis in particular [19–25]. Furthermore, plasma ascorbate correlates inversely with multiple organ failure [19] and directly with survival [21]."

"Inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta) inhibit ascorbate uptake in endothelial cell cultures that spontaneously express SVCT2 [34]. This action may deplete intracellular ascorbate from the endothelium during sepsis. A second reason why intracellular ascorbate may be depleted is the poor control of plasma glucose, which leads to episodes of hyperglycemia in septic patients [3]."

"Administering ascorbate parenterally rather than orally increases its effects on plasma ascorbate concentration and microvascular function [1]. For instance, when oral and intravenous routes of ascorbate administration (500 mg/day for 30 days) are compared in sedentary men, only intravenous ascorbate improves endothelium-dependent arteriolar function as indicated by flow-mediated vasodilation [47]."

"Parenteral administration of ascorbate may decrease morbidity and mortality in critically ill patients who are septic or at risk of becoming septic. In a randomized, double-blind, placebo-controlled trial with 216 critically ill patients, 28-day mortality was decreased in the patients who received combined ascorbate and vitamin E by intravenous infusion compared with those who did not [48]."

"A second randomized trial with 595 critically ill surgical patients found that a combination of ascorbate (1,000 mg q8h by intravenous injection) and vitamin E (1,000 IU q8h by naso- or orogastric tube), begun within 24 h of traumatic injury or major surgery, decreased relative risk of pulmonary edema and multiple organ failure [49]."

Antioxidants theoretically should be able to attenuate the effects of LPS exposure. Antioxidants in general if insufficient concentration can block the effects of multiple steps in endotoxin signalling. Multiple antioxidants have been demonstrated to block the production of NF-kB and also block the effects of the reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are produced by phagocytes in response to LPS. Vitamin C in particular has been shown to reduce the expression of iNOS in sepsis.

In sepsis patients plasma and cerebrospinal fluid ascorbate levels are decreased significantly. Several animal studies have also shown that sepsis depletes ascorbate levels in various tissues and that LPS decreases ascorbate uptake into cells. Because the bloodbrain barrier is compromised by LPS, sepsis patients commonly show neurological symptoms resulting from inflammation in the CNS, a septic encephalopathy .

Decreasing ascorbate concentrations in the CSF are directly correlated with the severity of neurological symptoms.

Please see the newsletter (courtesy of Biological Therapies) below for a fuller discussion of endotoxin and some of the potential roles of Vitamin C.