Shock/sepsis/trauma/critical careEffects of glycine, pyruvate, resveratrol, and nitrite on tissue injury and cytokine response in endotoxemic rats
Introduction
Sepsis and septic shock are the most common cause of death in intensive care units around the world [1]. Septic shock is the final result of complex interactions between the host immune response and infecting pathogens and defined as sepsis accompanied by hypotension that persists despite adequate resuscitation with fluids [2].
Lipopolysaccharide (LPS), a glycolipid of the outer membrane of Gram-negative bacteria, is a well-known pathogenic compound in septic shock that has been used in numerous experimental studies to induce acute inflammatory shock reactions [3], [4]. LPS induces a massive release of cytokines and other proinflammatory and anti-inflammatory mediators [5], [6], [7] and also leads to microvascular oxygen shortage because of an activation of the intravascular coagulation cascade [8], [9], [10] and arterial hypotension [11]. Consequently, tissue ischemia is a decisive pathogenic factor in LPS-induced shock.
We and others have demonstrated that the amino acids glycine, the end product of aerobic glycolysis, pyruvate, the plant polyphenol resveratrol, and nitrite have anti-inflammatory, cytoprotective, and immunomodulatory properties providing protection in several models of ischemia–reperfusion [12], [13], [14], [15], [16], [17], [18] and/or endotoxemia [19], [20], [21], [22], [23], [24], [25]. However, although many promising qualities have been reported for these compounds, no attempt has been made so far to compare their protective potentials in acute LPS-induced shock and assess whether inhibition of the proinflammatory cytokine response is a prerequisite for their protective actions when administered at low intravenous doses.
To this end, in the present study, we compare the tissue protective and systemic effects, as well as influences on the cytokine network of low doses of glycine, pyruvate, resveratrol, and nitrite, that is, doses we recently found to be most protective against mesenteric ischemia–reperfusion injury, in a rat model of acute systemic inflammation and shock induced by intravenous LPS.
Section snippets
Chemicals
Sodium pyruvate, resveratrol, and LPS (E. coli, serotype O111:B4; LOT: 099K4025) were obtained from Sigma-Aldrich (St. Louis, MO). Glycine was obtained from SERVA (Heidelberg, Germany), sodium nitrite from Merck (Darmstadt, Germany), isoflurane (Florene) from Abbott (Wiesbaden, Germany), ketamine 10% from CEVA (Düsseldorf, Germany), lidocaine (Xylocain 1%) from Astrazeneca (Wedel, Germany), and Ringer's solution from Fresenius Kabi (Bad Homburg, Germany). Portex catheters (0.58 mm inner
Results
The first of two consecutively performed series was conducted to assess the effects of glycine, sodium pyruvate, resveratrol, and sodium nitrite infusions on final parameters of LPS-induced tissue injury and inflammation at the end of the experiments (300 min after LPS administration).
Discussion
The present study demonstrates that in acute LPS-induced shock in rats, plasma markers of organ injury (cell death) and function (Fig. 6) are significantly improved by low-dose infusions of glycine (LDH, ALT, AST, CK-NAC, and creatinine), pyruvate (LDH and CK-NAC), resveratrol (LDH, AST, CK-NAC, and creatinine), and nitrite (LDH, ALT, AST, and CK-NAC), whereas none of the compounds decreased LPS-induced hemolysis (Fig. 3). Histopathologic markers of organ injury were not (heart and lung) or
Conclusion
In conclusion, in a rat model of acute LPS-induced systemic inflammation and shock, low doses of intravenous glycine, pyruvate, resveratrol, and nitrite improved both the MAP and plasma markers of organ injury (cell death) and function. Inhibition of the anti-inflammatory cytokine response seems to be not mandatory for these protective actions, which, instead, can be explained by features that diminish LPS-induced tissue ischemia (e.g., by improving microvascular perfusion) or directly protect
Acknowledgment
The authors thank Ms. Natalie Boschenkov for her excellent technical assistance.
References (49)
- et al.
The pathophysiology of septic shock
Crit Care Clin
(2009) - et al.
Lipopolysaccharide: biosynthetic pathway and structure modification
Prog Lipid Res
(2010) - et al.
Animal models of sepsis
Crit Care Clin
(2009) - et al.
Therapeutic strategies targeting the LPS signaling and cytokines
Pathophysiology
(2009) Nitric oxide in septic shock
Biochim Biophys Acta
(1999)- et al.
Protection by pyruvate infusion in a rat model of severe intestinal ischemia-reperfusion injury
J Surg Res
(2011) - et al.
Protection against severe intestinal ischemia/reperfusion injury in rats by intravenous resveratrol
J Surg Res
(2011) - et al.
Pyruvate protects against experimental stroke via an anti-inflammatory mechanism
Neurobiol Dis
(2009) - et al.
Resveratrol, a red wine polyphenol, attenuates lipopolysaccharide-induced oxidative stress in rat liver
Ecotoxicol Environ Saf
(2010) - et al.
Resveratrol attenuates lipopolysaccharide-induced hepatitis in d-galactosamine sensitized rats: role of nitric oxide synthase 2 and heme oxygenase-1
Nitric Oxide
(2009)
Proinflammatory cytokines
Chest
Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids
Anal Biochem
An evaluation of methods for grading histologic injury following ischemia/reperfusion of the small bowel
Transplant Proc
Prevention of lipopolysaccharide-induced mouse lethality by resveratrol
Food Chem Toxicol
Inhibition of cancer growth by resveratrol is related to its low bioavailability
Free Radic Biol Med
Current management of sepsis in critically ill adult patients
Expert Rev Anti Infect Ther
Chemoprevention with phytochemicals targeting inducible nitric oxide synthase
Forum Nutr
The interactions between inflammation and coagulation
Br J Haematol
Thrombocyte and erythrocyte indices in sepsis and disseminated intravascular coagulation
J Med Biochem
The immunopathogenesis of sepsis
Nature
The response of the host microcirculation to bacterial sepsis: does the pathogen matter?
J Mol Med
Protection from glycine at low doses in ischemia-reperfusion injury of the rat small intestine
Eur Surg Res
The role of glycine in hepatic ischemia-reperfusion injury
Curr Pharm Des
Resveratrol, a natural antioxidant attenuates intestinal ischemia/reperfusion injury in rats
Tohoku J Exp Med
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