title: Acute lethal crush-injured rats can be successfully rescued by a single injection of high-dose dexamethasone through a pathway involving PI3K-Akt-eNOS signaling.
abstract: BACKGROUND
  Crush syndrome (CS) is characterized by ischemia/reperfusion-induced rhabdomyolysis and the subsequent onset of systemic inflammation. CS is associated with a high mortality, even when patients are treated with conventional therapy. We hypothesized that treatment of lethal CS rat model with dexamethasone (DEX) have therapeutic effects on the laboratory findings and clinical course and outcome.
  
  
  METHODS
  To create a CS model, anesthetized rats were subjected to bilateral hind limb compression with rubber tourniquets for 5 hours and randomly divided into three groups as follows: saline-treated CS group, CS groups treated with low (0.1 mg/kg) and high doses (5.0 mg/kg) of DEX. Saline for the CS group or DEX for the DEX-treated CS groups was intravenously administered immediately before reperfusion. Under continuous monitoring and recording of arterial blood pressures, blood and tissue samples were collected for histologic and biochemical analysis at designated period before and after reperfusion.
  
  
  RESULTS
  Ischemic compression of rat hind limbs reduced the nitrite content in the crushed muscle, and the subsequent reperfusion induced reactive oxygen species-mediated circulatory collapse and systemic inflammation, finally resulting in a mortality rate of 76% by 48 hours after reperfusion. A single injection of high-dose DEX immediately before reperfusion activated endothelial nitric oxide synthase (eNOS) by sequential phosphorylation through the nongenomic phosphoinositide 3-kinase (PI3K)-Akt-eNOS signaling pathway. DEX also exhibited anti-inflammatory effects by modulating proinflammatory and anti-inflammatory mediators, consequently suppressing myeloperoxidase activities and subsequent systemic inflammation, showing a complete recovery of the rats from lethal CS.
  
  
  CONCLUSIONS
  These results indicate that high-dose DEX reduces systemic inflammation and contributes to the improved survival rate in a rat CS model.
authors.affiliation: Laboratory of Drug Safety Management, Department of Clinical Dietetics and Human Nutrition, Josai University, Saitama, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Murata
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ooi
authors.forename: Shingo
authors.initials: S
authors.lastname: Shoji
authors.forename: Yohei
authors.initials: Y
authors.lastname: Motohashi
authors.forename: Miwa
authors.initials: M
authors.lastname: Kan
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ohtake
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.forename: Hideo
authors.initials: H
authors.lastname: Ueda
authors.forename: Genya
authors.initials: G
authors.lastname: Nakano
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Sonoda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uchida
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kanamoto
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Morimoto
authors.forename: Jun
authors.initials: J
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D003444:Crush Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D015850:Interleukin-6; D016753:Interleukin-10; D003907:Dexamethasone; D009195:Peroxidase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt