TY - JOUR
T1 - Pretreatment strategy with adenosine A2A receptor agonist attenuates reperfusion injury in a preclinical porcine lung transplantation model
AU - Lapar, Damien J.
AU - Laubach, Victor E.
AU - Emaminia, Abbas
AU - Crosby, Ivan K.
AU - Hajzus, Vanessa A.
AU - Sharma, Ashish K.
AU - Sumner, Heather M.
AU - Webb, David V.
AU - Lau, Christine L.
AU - Kron, Irving L.
N1 - Funding Information:
This study was supported by a research grant from the Roche Organ Transplant Research Foundation, Meggen, Switzerland (to V.E.L.) and by National Institutes of Health Grant T32HL007849 (to I.L.K.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or the National Institutes of Health.
PY - 2011/10
Y1 - 2011/10
N2 - Objective: Adenosine A2A receptor activation after lung transplantation attenuates ischemia-reperfusion injury by reducing inflammation. However, the effect of adenosine A2A receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A2A receptor agonist in a clinically relevant porcine lung transplantation model. Methods: Mature porcine lungs underwent 6 hours of cold ischemia before allotransplantation and 4 hours of reperfusion. Five groups (n = 6/group) were evaluated on the basis of treatment with ATL-1223, a selective adenosine A2A receptor agonist: thoracotomy alone (sham), transplant alone (ischemia-reperfusion), donor pretreatment via ATL-1223 bolus (ATL-D), recipient treatment via ATL-1223 infusion (ATL-R), and a combination of both ATL-1223 treatments (ATL-D/R). Lung function and injury were compared. Results: Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus ischemia-reperfusion (392.0 ± 52.5, 428.9 ± 25.5, and 509.4 ± 25.1 vs 77.2 ± 17.0 mm Hg, respectively, P < .001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D = 30.5 ± 1.8, ATL-R = 30.2 ± 3.3, and ATL-D/R = 29.3 ± 4.5 vs IR = 45.2 ± 2.1 mm Hg, P < .001) and lower mean airway pressures versus ischemia-reperfusion (ATL-D = 9.1 ± 0.8, ATL-R = 9.1 ± 2.6, and ATL-D/R = 9.6 ± 1.3 vs IR = 21.1 mm Hg, P < .001). Likewise, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression, and lung injury scores by histology compared with ischemia-reperfusion. All parameters of lung function and injury in ATL-1223-treated groups were similar to sham (all P >.05). Conclusions: Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against ischemia-reperfusion injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A2AR agonists for use in human clinical trials for lung transplantation.
AB - Objective: Adenosine A2A receptor activation after lung transplantation attenuates ischemia-reperfusion injury by reducing inflammation. However, the effect of adenosine A2A receptor activation in donor lungs before transplant remains ill defined. This study compares the efficacy of 3 different treatment strategies for adenosine A2A receptor agonist in a clinically relevant porcine lung transplantation model. Methods: Mature porcine lungs underwent 6 hours of cold ischemia before allotransplantation and 4 hours of reperfusion. Five groups (n = 6/group) were evaluated on the basis of treatment with ATL-1223, a selective adenosine A2A receptor agonist: thoracotomy alone (sham), transplant alone (ischemia-reperfusion), donor pretreatment via ATL-1223 bolus (ATL-D), recipient treatment via ATL-1223 infusion (ATL-R), and a combination of both ATL-1223 treatments (ATL-D/R). Lung function and injury were compared. Results: Blood oxygenation was significantly higher among ATL-D, ATL-R, and ATL-D/R groups versus ischemia-reperfusion (392.0 ± 52.5, 428.9 ± 25.5, and 509.4 ± 25.1 vs 77.2 ± 17.0 mm Hg, respectively, P < .001). ATL-1223-treated groups had lower pulmonary artery pressures (ATL-D = 30.5 ± 1.8, ATL-R = 30.2 ± 3.3, and ATL-D/R = 29.3 ± 4.5 vs IR = 45.2 ± 2.1 mm Hg, P < .001) and lower mean airway pressures versus ischemia-reperfusion (ATL-D = 9.1 ± 0.8, ATL-R = 9.1 ± 2.6, and ATL-D/R = 9.6 ± 1.3 vs IR = 21.1 mm Hg, P < .001). Likewise, ATL-1223-treated groups had significantly lower lung wet/dry weight, proinflammatory cytokine expression, and lung injury scores by histology compared with ischemia-reperfusion. All parameters of lung function and injury in ATL-1223-treated groups were similar to sham (all P >.05). Conclusions: Pretreatment of donor lungs with ATL-1223 was as efficacious as other treatment strategies in protecting against ischemia-reperfusion injury. If necessary, supplemental treatment of recipients with ATL-1223 may provide additional protection. These results support the development of pharmacologic A2AR agonists for use in human clinical trials for lung transplantation.
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U2 - 10.1016/j.jtcvs.2011.06.015
DO - 10.1016/j.jtcvs.2011.06.015
M3 - Article
C2 - 21762933
AN - SCOPUS:80052853547
VL - 142
SP - 887
EP - 894
JO - Journal of Thoracic and Cardiovascular Surgery
JF - Journal of Thoracic and Cardiovascular Surgery
SN - 0022-5223
IS - 4
ER -