title: Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock.
abstract: Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-kappaB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.
authors.affiliation: Department of Critical Care Medicine, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Runkuan
authors.initials: R
authors.lastname: Yang
authors.forename: David J
authors.initials: DJ
authors.lastname: Gallo
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Baust
authors.forename: Takashi
authors.initials: T
authors.lastname: Uchiyama
authors.forename: Simon K
authors.initials: SK
authors.lastname: Watkins
authors.forename: Russell L
authors.initials: RL
authors.lastname: Delude
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Fink
mesh_terms: D000818:Animals; D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects*; D007249:Inflammation / Q000235:genetics*; D007413:Intestinal Mucosa / Q000503:physiopathology; D007552:Isotonic Solutions / Q000494:pharmacology*; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012151:Resuscitation; D000077325:Ringer's Lactate; D012771:Shock, Hemorrhagic / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D016019:Survival Analysis
chemical_list: D007552:Isotonic Solutions; D016328:NF-kappa B; D000077325:Ringer's Lactate; C439503:Ringer's ethyl pyruvate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse