title: MCI-186 (edaravone), a free radical scavenger, attenuates ischemia-reperfusion injury and activation of phospholipase A(2) in an isolated rat lung model after 18 h of cold preservation.
abstract: OBJECTIVE
  Increased microvascular permeability and extravasation of inflammatory cells are key events in ischemia-reperfusion (IR) injury. We hypothesized that edaravone, a free radical scavenger, is able to attenuate IR lung injury by decreasing oxidative stress and phospholipase A(2) (PLA(2)) activation, which otherwise may lead to lung injury through PAF receptor (PAF-R) activation.
  
  
  METHODS
  We used an isolated rat lung model. Five groups were defined (n=7, each): in the sham and vehicle group, lungs were immediately washed after thoracotomy or perfused for 2h without an ischemic period, respectively. In the ischemic groups, 10mg/kg of MCI-186 (edavorane group), 1mg/kg of PAF-R inhibitor (ABT-491 group) or saline (control group) were i.v. administered 20 min before harvest. Lungs were flushed with LPD solution, stored at 4 degrees C for 18 h, and reperfused for 2h.
  
  
  RESULTS
  Compared to vehicle group, IR significantly decreased the PO(2) level and increased the wet-to-dry ratio, proteins in bronchoalveolar lavage (BAL), and myeloperoxidase (MPO) activity in the control group, while edaravone treatment maintained the PO(2) similar to the vehicle group and significantly reduced edema formation and neutrophil extravasation. Consistently, IR significantly increased lipid peroxidation, cytosolic-PLA(2) activity mainly via alveolar macrophages, soluble-PLA(2) activity, leukotriene B(4), and PAF-R expression in control lungs, together with a decreased PAF acetylhydrolase (PAF-AH) activity. Edaravone significantly reduced all of these, but increased PAF-AH activity. Furthermore, pharmacological inhibition of the PAF-R attenuated IR injury resembling edaravone action.
  
  
  CONCLUSIONS
  Edaravone attenuates lung IR injury by suppressing oxidative damage and PLA(2) activation, which otherwise partially mediates edema formation and neutrophil extravasation through PAF-R activation.
authors.affiliation: Department of Cardio-thoracic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Yury A Bellido
authors.initials: YA
authors.lastname: Reyes
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shimoyama
authors.forename: Hideki
authors.initials: H
authors.lastname: Akamatsu
authors.forename: Makoto
authors.initials: M
authors.lastname: Sunamori
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D050377:Cold Ischemia; D004195:Disease Models, Animal; D000077553:Edaravone; D004487:Edema / Q000517:prevention & control; D004789:Enzyme Activation; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000098:blood supply*; D008297:Male; D009924:Organ Culture Techniques; D009926:Organ Preservation / Q000379:methods; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D010741:Phospholipases A / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D016166:Free Radical Scavengers; D010741:Phospholipases A; D000077553:Edaravone; D010100:Oxygen; D000983:Antipyrine