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Clodronate-liposome is used for depleting mononuclear phagocytes associated with ischemia-reperfusion injury. We hypothesized that administration of clodronate-liposome into the perfusate during ex vivo lung perfusion could reduce mononuclear phagocytes and attenuate ischemia-reperfusion injury.First, the number of mononuclear phagocytes in flushed grafts (minimum cold ischemic time, 6-hour cold ischemic time, 15-hour cold ischemic time, and 18-hour cold ischemic time; n = 6 each) was determined using flow cytometry. Second, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 5 each). In the clodronate group, clodronate-liposome is administered into the perfusate. After 4 hours of ex vivo lung perfusion, the number of mononuclear phagocytes in the perfusate and lung tissues was measured. Third, grafts (15-hour cold ischemic time) were allocated to control or clodronate (n = 6 each). After 4 hours of ex vivo lung perfusion, the left lungs were transplanted and reperfused for 2 hours. Lung function was evaluated, and samples were analyzed.First, mononuclear phagocytes remain in flushed grafts after prolonged cold ischemia. Second, the number of mononuclear phagocytes in lung tissues after ex vivo lung perfusion was significantly reduced in the clodronate group (P = .008). Third, lung compliance and vascular resistance during ex vivo lung perfusion were significantly improved in the clodronate group (P .001 for both). Blood oxygenation and pulmonary edema were significantly improved in the clodronate group after 2 hours of reperfusion (P = .015 and P = .026, respectively). Histological findings showed reduced lung injury in the clodronate group (P = .013).Administration of clodronate-liposome into the perfusate during ex vivo lung perfusion resulted in a significant reduction of mononuclear phagocytes in donor lungs, leading to attenuation of ischemia-reperfusion injury.

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.