Reduction of donor mononuclear phagocytes with clodronate-liposome during ex vivo lung perfusion attenuates ischemia-reperfusion injury

Objectives: 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.Methods: 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. Sec -ond, 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. Results: 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 oxygen-ation and pulmonary edema were significantly improved in the clodronate group after 2 hours of reperfusion (P = .015 and P = .026, respectively). Histological find-ings showed reduced lung injury in the clodronate group (P = .013).Conclusions: Administration of clodronate-liposome into the perfusate during ex vivo lung perfusion resulted in a significant reduction of mononuclear phago-cytes in donor lungs, leading to attenuation of ischemia-reperfusion injury. (J Thorac Cardiovasc Surg 2023;165:e181-203)

Automated summary

The objective of this study was to investigate the depletion of mononuclear phagocytes and the attenuation of ischemia-reperfusion injury by clodronate-liposome during ex vivo lung perfusion. The experiments determined the number of mononuclear phagocytes in flushed grafts using flow cytometry and administered clodronate-liposome into the perfusate during ex vivo lung perfusion. The results showed a significant reduction in the number of mononuclear phagocytes in the clodronate group, improved lung function, and reduced lung injury.