Adenosine A2A receptor activation decreases reperfusion injury associated with high-flow reperfusion.
BACKGROUND
High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A(2A) receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion.


METHODS
Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 microg. kg(-1). min(-1).


RESULTS
ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes.


CONCLUSIONS
The adenosine A(2A) receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.
Fiser
Steven M
SM
Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA. smf9e@virginia.edu
Tribble
Curtis G
CG
Kaza
Aditya K
AK
Long
Stewart M
SM
Kern
John A
JA
Cassada
David C
DC
Linden
Joel
J
Rieger
Jayson
J
Laubach
Victor E
VE
Matisoff
Andy
A
Kron
Irving L
IL
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D008168:Lung / Q000201:enzymology / Q000378:metabolism / Q000601:surgery; D008297:Male; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000737:chemistry / Q000473:pathology; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011687:Purines / Q000494:pharmacology*; D011817:Rabbits; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000627:therapeutic use*; D015424:Reperfusion / Q000009:adverse effects*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D013997:Time Factors
C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D009195:Peroxidase