Ence, chemotaxis, ingestion and O2?anion production [31]. Furthermore, ascorbate has profound
Ence, chemotaxis, ingestion and O2?anion production [31]. Furthermore, ascorbate has profound bacteriostatic activity. Ascorbate (in concentrations from 100 to 1,000 M) significantly inhibited bacterial replication in dilute fecal samples in vitro [32].Oudemans-van Straaten et al. Critical Care 2014, 18:460 http://ccforum.com/content/18/1/Page 4 ofRole of vitamin C: animal studiesIschemia/reperfusionBeneficial effects of ascorbate pretreatment on organ function were observed in ischemia reperfusion injury models of rat heart [33] and rabbit kidney [34], and of rat skeletal muscle [35,36], lung [37] and liver [38-41]. Studies are summarized in Table 1. In a rat model of cardiac arrest (ventricular fibrillation and electrical shock), intravenous ascorbate at the start of resuscitation alleviated postcardiac arrest myocardial necrosis and mitochondrial damage, reduced lipid peroxidation and improved the resuscitation success rate and 72-hour survival [33]. In a pig model of coronary artery ischemia/reperfusion and preconditioning, intravenous ascorbate started 30 minutes before ischemic preconditioning or ischemia had no effect on infarct size, but abolished the reduction in infarct size by ischemic preconditioning [42]. In a rabbit renal ischemia model, ascorbate ameliorated renal structure and function [34]. Ascorbate also had a positive effect on muscle injury when administered intravenously (i.v.) during ischemia/reperfusion of the leg in rats [36]. Experiments with different intravenous ascorbate doses to rats prior to hepatic ischemia reperfusion found antioxidant effects at low and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/27597769 moderate doses and predominant pro-oxidant effects at extremely high doses (1,000 mg/kg) [38]. In addition, vitamin C administered after ischemic preconditioning but before clamping of the liver blood flow reduced hepatic mitochondrial damage and dysfunction [41]. Thus, in these animal models, ascorbate reduced ischemic organ injury and improved function, but abolished the protective effects of ischemic preconditioning on organ injury.Sepsismechanism when administered 6 hours after FIP [44,47]. In addition, ascorbate (200 mg/kg i.v.) administration before CLP protected against impaired arteriolar constriction and loss of catecholamine responsiveness and improved 24-hour survival in mice [6,48]. Ascorbate prevented arteriolar vasoconstriction by inhibiting eNOS uncoupling and iNOS-derived and neuronal SB 202190MedChemExpress SB 202190 nitric oxide synthase-derived NO production, when given before but also 3 hours after CLP in mice [48-50]. Moreover, ascorbate (200 mg/kg i.v.) prevented vascular leakage in a mouse CLP model by inhibiting excessive production of NO by iNOS and neuronal nitric oxide synthase, and of O2?by NOX, and by inhibiting the activation of protein phosphatase 2A, thereby preserving occludin phosphorylation [50]. Ascorbate thus restored several seemingly contradictory disorders contributing the heterogeneity of the septic circulation. Ascorbate improved microcirculatory perfusion by NOX inhibition and arteriolar vasodilator responsiveness (neuronal nitric oxide synthase related), restored vasoconstrictor responsiveness by inhibiting iNOS expression and prevented vascular leakage.Effects on organ injury and functionThe most frequently used sepsis animal models are feces injection into the peritoneum (FIP), cecal ligation and puncture (CLP) and intraperitoneal injection of LPS.Ascorbate depletionAscorbate plasma concentrations rapidly declined in lymphocytes and macrophage.