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.
Highlights
Local infectious or non-infectious insult can lead to a systemic inflammatory response
Both effects of ascorbate could explain its ability to protect against hypotension in sepsis
Because sepsis increases the level of reactive oxygen species (ROS) in skeletal muscle [26], and heat shock protein 90 (HSP 90) protein expression increases in response to ROS [37], ascorbate could scavenge ROS, prevent HSP 90 protein up-regulation, inhibit sepsis-induced increased neuronal NOS (nNOS) activity and NO production, and prevent the septic impairment of arteriolar conduction [29]
Summary
Local infectious or non-infectious insult can lead to a systemic inflammatory response. A recent clinical study including the septic elderly reported markedly improved survival in patients injected intravenously with vitamin C, hydrocortisone and thiamine [16]. This improved survival is consistent with that observed in septic mice injected with ascorbate [15,17,18]. The sepsis-induced inflammatory response leads to dysfunction of many organ systems, including the cardiovascular system where decreased systemic vascular resistance, hypotension, maldistribution of blood flow in the microcirculation, and impaired oxygen utilization occur [19,20]. Using various animal models of sepsis, our laboratory has examined the dysfunction of the microcirculation, and the possible beneficial effects of intravenous injection of ascorbate against this dysfunction. The objective of the present paper is to review these advances
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