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.
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.
Reyes
Yury A Bellido
YA
Department of Cardio-thoracic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan.
Shimoyama
Takehiko
T
Akamatsu
Hideki
H
Sunamori
Makoto
M
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*
D016166:Free Radical Scavengers; D010741:Phospholipases A; D000077553:Edaravone; D010100:Oxygen; D000983:Antipyrine