Specialized Proresolving Lipid Meditators Agonistic to Formyl Peptide Receptor Type 2 Attenuate Ischemia-reperfusion Injury in Rat Lung.

Abstract

Lung ischemia-reperfusion injury (IRI) is a form of acute lung injury characterized by nonspecific alveolar damage and lung edema due to robust inflammation. Little is known about the roles of specialized proresolving lipid mediators (SPMs) in lung IRI. Therefore, we aimed to evaluate the dynamic changes in endogenous SPMs during the initiation and resolution of lung IRI and to determine the effects of SPM supplementation on lung IRI. We used a rat left hilar clamp model with 90 min of ischemia, followed by reperfusion. Dynamic changes in endogenous SPMs were evaluated using liquid chromatography-tandem mass spectrometry. Endogenous SPMs in the left lung showed a decreasing trend after 1 h of reperfusion. Oxygenation improved between 3 and 7 d following reperfusion; however, the level of endogenous SPMs remained low compared with that in the naïve lung. Among SPM receptors, only formyl peptide receptor type 2 (ALX/FPR2) gene expression in the left lung was increased 3 h after reperfusion, and the inflammatory cells were immunohistochemically positive for ALX/FPR2. Administration of aspirin-triggered (AT) resolvin D1 (AT-RvD1) and AT lipoxin A4 (AT-LXA4), which are agonistic to ALX/FPR2, immediately after reperfusion improved lung function, reduced inflammatory cytokine levels, attenuated lung edema, and decreased neutrophil infiltration 3 h after reperfusion. The effects of AT-RvD1 and AT-LXA4 were not observed after pretreatment with the ALX/FPR2 antagonist. The level of intrapulmonary endogenous SPMs decreased during lung IRI process and the administration of AT-RvD1 and AT-LXA4 prevented the exacerbation of lung injury via ALX/FPR2.