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Eur J Cardiothorac Surg 2006;29:304-311
© 2006 Elsevier Science NL

MCI-186 (edaravone), a free radical scavenger, attenuates ischemia–reperfusion injury and activation of phospholipase A₂ in an isolated rat lung model after 18 h of cold preservation

Department of Cardio-thoracic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8519, Japan

Received 10 September 2005; received in revised form 14 November 2005; accepted 2 December 2005.

^_* Corresponding author. Tel.: +81 3 5803 5267; fax: +81 3 5803 0141. (Email: sunamori.tsrg{at}tmd.ac.jp).

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 A₂ (PLA₂) 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 2 h without an ischemic period, respectively. In the ischemic groups, 10 mg/kg of MCI-186 (edavorane group), 1 mg/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 °C for 18 h, and reperfused for 2 h. Results: Compared to vehicle group, IR significantly decreased the PO₂ 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 PO₂ similar to the vehicle group and significantly reduced edema formation and neutrophil extravasation. Consistently, IR significantly increased lipid peroxidation, cytosolic-PLA₂ activity mainly via alveolar macrophages, soluble-PLA₂ activity, leukotriene B₄, 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. Conclusion: Edaravone attenuates lung IR injury by suppressing oxidative damage and PLA₂ activation, which otherwise partially mediates edema formation and neutrophil extravasation through PAF-R activation.

Key Words: Edaravone • Phospholipase A₂ • Lung • Ischemia–reperfusion