title: Ethyl pyruvate diminishes the inflammatory response to lipopolysaccharide infusion in horses.
abstract: BACKGROUND
  Endotoxaemia contributes to morbidity and mortality in horses with colic due to inflammatory cascade activation. Effective therapeutic interventions are limited for these horses. Ethyl pyruvate (EP), an anti-inflammatory agent that alters the expression of proinflammatory cytokines, improved survival and organ function in sepsis and gastrointestinal injury in rodents and swine. Therapeutic efficacy of EP is unknown in endotoxaemic horses.
  
  
  OBJECTIVE
  Determine the effects of EP on signs of endotoxaemia and expression of proinflammatory cytokines following administration of lipopolysaccharide (LPS) in horses.
  
  
  METHODS
  Horses received 30 ng/kg bwt LPS in saline to induce signs of endotoxaemia. Next, horses received lactated Ringer's solution (LRS), (n = 6), 150 mg/kg bwt EP in LRS, (n = 6), or 1.1 mg/kg bwt flunixin meglumine (FM), (n = 6). Controls received saline followed by LRS (n = 6). Physical examinations, behaviour pain scores and blood for clinical pathological testing and gene expression were obtained at predetermined intervals for 24 h.
  
  
  RESULTS
  Lipopolysaccharide infusion produced clinical and clinicopathological signs of endotoxaemia and increased expression of tumour necrosis factor alpha (TNFα), interleukin 6 (IL-6) and IL-8 (P<0.001) compared with controls. Leucopenia and neutropenia occurred in all horses that received LPS. Horses treated with EP and FM had significantly (P<0.0001) reduced pain scores compared with horses receiving LPS followed by LRS. Flunixin meglumine was significantly more effective at ameliorating fever compared with EP. Both EP and FM significantly diminished TNFα expression. Ethyl pyruvate significantly decreased, but FM significantly increased, IL-6 expression. Neither EP nor FM altered IL-8 expression.
  
  
  CONCLUSIONS
  Ethyl pyruvate administered following LPS diminished the clinical effects of endotoxaemia and decreased proinflammatory gene expression in horses. Ethyl pyruvate suppressed expression of proinflammatory cytokines better than FM. However, FM was a superior anti-pyretic compared with EP. Ethyl pyruvate may have therapeutic applications in endotoxaemic horses.
authors.affiliation: Departments of Large, College of Veterinary Medicine, Michigan State University, East Lansing, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Jacobs
authors.forename: S J
authors.initials: SJ
authors.lastname: Holcombe
authors.forename: V L
authors.initials: VL
authors.lastname: Cook
authors.forename: J C
authors.initials: JC
authors.lastname: Gandy
authors.forename: J G
authors.initials: JG
authors.lastname: Hauptman
authors.forename: L M
authors.initials: LM
authors.lastname: Sordillo
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D003002:Clonixin / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006734:Horse Diseases / Q000139:chemically induced* / Q000188:drug therapy; D006736:Horses; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000662:veterinary*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D011773:Pyruvates / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D011773:Pyruvates; D014409:Tumor Necrosis Factor-alpha; C046522:ethyl pyruvate; C014558:flunixin meglumine; D003002:Clonixin