Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation

Abstract

Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.

Thoracic organ machine perfusion: A review of concepts with a focus on reconditioning therapies

“…This explanation seems particularly applicable in the study by Hozain et al given that the steady decrease of inflammatory cytokines as measured in broncheoalveolar lavage (BAL) along with reduced leukocyte infiltrate could be most associated with the functional benefit to the lung during cross circulation (128). This is reinforced by other studies, whereby cytokine adsorbers utilized to sequester the inflammatory mileu were associated with improved lung function, edema formation, and reduced incidence of PGD following EVLP (135,136). It is also known that DAMPs, also released during IRI, steadily increase over the course of EVLP, and are associated with increased TNF-α secretion as a downstream result of DAMP induced signalling (81,137).…”

Primary Graft Dysfunction in Lung Transplantation: A Review of Mechanisms and Future Applications

“…In a pig lung transplant model in which donor lungs were injured by endotoxin administration, cytokine adsorption treatment during EVLP resulted in lower proinflammatory cytokine levels in perfusate, better graft function, and fewer histologic signs of injury in treated versus untreated lungs. 77 Alpha-1 antitrypsin is known to possess immunomodulatory properties, and when used to treat pig lungs on EVLP after a 24-h cold ischemic period, the physiological parameters were better in the treated lungs, and inflammation marker levels were lower. 78 As discussed in the Molecular Mechanisms section above, activating the coagulation and complement systems after ischemia–reperfusion contributes to PGD.…”

“…In a pig lung transplant model in which donor lungs were injured by endotoxin administration, cytokine adsorption 75 Reperfusion FiO 2 <40% Lower ROS-induced lipid peroxidation and less PGD Shaver et al 76 Reperfusion FiO 2 <40% Higher reperfusion FiO 2 (95%) amplified CFH-mediated injury Ghaidan et al 77 Cytokine adsorption during EVLP in a pig model Improved graft function after transplant Lin et al 78 Alpha-1 antitrypsin treatment during EVLP in a pig model Lower injury marker levels and better graft function Motoyama et al 79 Plasmin treatment during EVLP in a rat model Improved physiological parameters and less histologic injury Keshavjee et al 80 TP-10 (complement inhibitor) in RCT Shorter duration of mechanical ventilation posttransplant Sommer et al 81 C1-esterase inhibitor in a clinical trial for PGD Better oxygenation, shorter ICU stay, and trend toward longer survival Emaminia et al 41,82 Adenosine A 2A agonism during EVLP in a pig model Less edema and better oxygenation with lower airway pressures Noda et al 83 Hydrogen gas during EVLP in a rat model Better graft function, downregulated IL-6, IL-1β, and TNF-α transcripts Inci et al 84 Surfactant instillation in a pig transplant model Better oxygenation and less neutrophil infiltration Inci et al 85 Surfactant instillation during EVLP in a pig model Better graft function, less pulmonary edema, and less BAL neutrophilia treatment during EVLP resulted in lower proinflammatory cytokine levels in perfusate, better graft function, and fewer histologic signs of injury in treated versus untreated lungs. 77 Alpha-1 antitrypsin is known to possess immunomodulatory properties, and when used to treat pig lungs on EVLP after a 24-h cold ischemic period, the physiological parameters were better in the treated lungs, and inflammation marker levels were lower. 78 As discussed in the Molecular Mechanisms section above, activating the coagulation and complement systems after ischemia-reperfusion contributes to PGD.…”

Diagnostic and Therapeutic Implications of Ex Vivo Lung Perfusion in Lung Transplantation: Potential Benefits and Inherent Limitations

“…79 In addition to these adverse effects of cold preservation, EVLP itself also generates a negative proinflammatory environment, which can be eliminated via leukocyte-depleting filtration, neutrophil elastase inhibition, triptolide administration, and cytokine adsorption. [80][81][82][83] Thus, the clinical application of these anti-inflammatory strategies during EVLP is eagerly awaited.…”