Effects of Warm versus Cold Ischemic Donor Lung Preservation on the Underlying Mechanisms of Injuries during Ischemia and Reperfusion

ABSTRACTBackgroundIschemia-reperfusion injury related to lung transplantation is a major contributor to early postoperative morbidity and mortality. We hypothesized that donation after cardiac death donor lungs experience warm ischemic conditions that activate different injurious mechanisms compared with donor lungs that undergo prolonged cold ischemic conditions.MethodsRat donor lungs were preserved under different cold ischemic times (CIT: 12 hours or 18 hours), or under warm ischemia time (WIT: 3 hours) after cardiac death, followed by single left lung transplantation. Lung function was analyzed during the 2-hours reperfusion period. Microscopic injury, cell death, energy status and inflammatory responses were assessed.ResultsPulmonary oxygenation function was significantly worse in both 18hCIT and WIT groups, accompanied by higher peak airway pressure, acute lung injury scores and expression of cell death markers compared to the 12hCIT control group. In lung tissue, reperfusion induced increased expression levels of interleukin (IL)-1α, IL-1β, IL-6, and chemokines CCL2, CCL3, CXCL1, and CXCL2 in CIT lungs. Notably, these changes were much lower in the WIT group. Additionally, plasma levels of IL-6, IL-18, CCL2 and VEGF were significantly higher, and ATP levels were significantly reduced in warm versus cold ischemic lungs.ConclusionsCompared to 12hCIT, posttransplant pathophysiology deteriorated similarly in both 18hCIT and WIT groups. However, tissue ATP levels and inflammatory profiling differed between warm versus cold ischemic donor lungs. These differences should be carefully considered when developing specific therapeutic strategies to reduce ischemia reperfusion injury in lung transplantation. Background Ischemia-reperfusion injury related to lung transplantation is a major contributor to early postoperative morbidity and mortality. We hypothesized that donation after cardiac death donor lungs experience warm ischemic conditions that activate different injurious mechanisms compared with donor lungs that undergo prolonged cold ischemic conditions. Methods Rat donor lungs were preserved under different cold ischemic times (CIT: 12 hours or 18 hours), or under warm ischemia time (WIT: 3 hours) after cardiac death, followed by single left lung transplantation. Lung function was analyzed during the 2-hours reperfusion period. Microscopic injury, cell death, energy status and inflammatory responses were assessed. Results Pulmonary oxygenation function was significantly worse in both 18hCIT and WIT groups, accompanied by higher peak airway pressure, acute lung injury scores and expression of cell death markers compared to the 12hCIT control group. In lung tissue, reperfusion induced increased expression levels of interleukin (IL)-1α, IL-1β, IL-6, and chemokines CCL2, CCL3, CXCL1, and CXCL2 in CIT lungs. Notably, these changes were much lower in the WIT group. Additionally, plasma levels of IL-6, IL-18, CCL2 and VEGF were significantly higher, and ATP levels were significantly reduced in warm versus cold ischemic lungs. Conclusions Compared to 12hCIT, posttransplant pathophysiology deteriorated similarly in both 18hCIT and WIT groups. However, tissue ATP levels and inflammatory profiling differed between warm versus cold ischemic donor lungs. These differences should be carefully considered when developing specific therapeutic strategies to reduce ischemia reperfusion injury in lung transplantation. #Equally contributed Corresponding author: Shaf Keshavjee, MD, Address: Toronto General Hospital, 200 Elizabeth Street, Room 9N946, Toronto, ON M5G 2C4 Canada. Email: shaf.keshavjee@uhn.ca Authorship: I.I., M.Cy., T.K.W., M.L., and S.K. participated in the research design. I.I., M.Ch., J.S., H.K., K.Y., H.L., Z.G., and K.H. participated in the performance of the research. I.I., M.Cy., T.M., M.Ch., J.S., H.K., K.Y., and H.L. participated in data analysis and interpretation. I.I., M.Cy., T.M., M.Ch., K.H., T.K.W., M.L., and S.K. participated in writing and reviewing of the article. S.K. and M.L. directed the project. Disclosure: The authors declare no conflicts of interest. Funding: This study was supported by the Canadian Institutes of Health Research (operating grant # MOP-93740). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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