title: Hydrocortisone and the mitogen-activated protein kinase inhibitor U0126 acutely suppress reactive oxygen species generation from circulating granulocytes after gunshot injuries in the pig.
abstract: OBJECTIVE
  Several external stimuli, including trauma, increase the endogenous production of reactive oxygen species that spontaneously attack vital biological molecules. In addition to their direct toxic effects, several secondary messenger systems are induced. To forestall a subsequent organ dysfunction, a short-term posttraumatic down-regulation of granulocyte function has been advocated. Corticosteroids are potent and universal anti-inflammatory agents, but they have well-known side effects. Modulation of the mitogen-activated protein kinase cascade is an alternative approach. The purpose of this study was to investigate how the posttraumatic production of reactive oxygen species can be modulated by hydrocortisone or the extracellular signal-regulated kinase inhibitor U0126.
  
  
  METHODS
  Prospective randomized trial.
  
  
  METHODS
  Field hospital and research laboratory.
  
  
  METHODS
  Seventeen male pigs.
  
  
  METHODS
  In general anesthesia, the pigs were exposed to a standardized insult: one gunshot hitting the right femur from a distance of 25 m, and one pistol shot to the left upper abdomen from close range. Following immediate first aid treatment, the animals were transported to a nearby field hospital. According to randomization, the animals received either hydrocortisone 250 mg intravenously (group 1, n = 9) or a similar amount of saline (group 2, n = 8). The injections were given 5 mins after the last shot. Blood samples were drawn before shooting, immediately before hydrocortisone was given, and 60 mins after shooting. Circulating neutrophils were isolated, and the production of reactive oxygen species was measured fluorometrically. Neutrophils from nine randomly chosen animals (five from group 1 and four from group 2) were treated in vitro with the extracellular signal-regulated kinase inhibitor U0126.
  
  
  RESULTS
  The injuries as evaluated by the abbreviated injury scale did not differ between the animals. All survived the first 60 mins. While the in vivo production of reactive oxygen species tended to increase in the controls, a significant reduction was measured in the hydrocortisone group. Subsequent treatment with U0126 further reduced the synthesis of reactive oxygen species by about two thirds in both groups, independently of time.
  
  
  CONCLUSIONS
  Early injection of hydrocortisone after trauma inhibits the synthesis of reactive oxygen species from circulating neutrophils. Inhibition of the extracellular signal-regulated kinase branch of the mitogen-activated protein kinase signaling cascade is an alternative approach. The powerful in vitro capacity of selective extracellular signal-regulated kinase inhibitors to reduce the posttraumatic reactive oxygen species generation deserves further investigations, and compelling evidence of their in vivo usefulness is still lacking.
authors.affiliation: Division of Protection and Material, Norweigian Defense Research Establishment, Kjeller, Norway.
authors.forename: Yngvar
authors.initials: Y
authors.lastname: Gundersen
authors.forename: Per
authors.initials: P
authors.lastname: Vaagenes
authors.forename: Oddvar
authors.initials: O
authors.lastname: Myhre
authors.forename: Jannike Mørch
authors.initials: JM
authors.lastname: Andersen
authors.forename: Anne
authors.initials: A
authors.lastname: Pharo
authors.forename: Ann-Helen
authors.initials: AH
authors.lastname: Haugen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Valoe
authors.forename: Per Kristian
authors.initials: PK
authors.lastname: Opstad
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002070:Butadienes / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006854:Hydrocortisone / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D018375:Neutrophil Activation / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation; D017382:Reactive Oxygen Species / Q000097:blood*; D013552:Swine; D014948:Wounds, Gunshot / Q000097:blood / Q000188:drug therapy*
chemical_list: D000893:Anti-Inflammatory Agents; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D006854:Hydrocortisone