Adenosine A2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation.
BACKGROUND
Reperfusion injury continues to significantly affect patients undergoing lung transplantation. Isolated lung models have demonstrated that adenosine A 2A receptor activation preserves function while decreasing inflammation. We hypothesized that adenosine A 2A receptor activation by ATL-146e during the initial reperfusion period preserves pulmonary function and attenuates inflammation in a porcine model of lung transplantation.


METHODS
Mature pig lungs preserved with Viaspan (Barr Laboratories, Pomona, NY) underwent 6 hours of cold ischemia before transplantation and 4 hours of reperfusion. Animals were treated with (ATL group, n = 7) and without (IR group, n = 7) ATL-146e (0.05 microg kg -1 . min -1 ATL-146e administered intravenously for 3 hours). With occlusion of the opposite pulmonary artery, the animal was maintained for the final 30 minutes on the allograft alone. Recipient lung physiology was monitored before tissue evaluation of pulmonary edema (wet-to-dry weight ratio), myeloperoxidase assay, and tissue tumor necrosis factor alpha by means of enzyme-linked immunosorbent assay.


RESULTS
When the ATL group was compared with the IR group, the ATL group had better partial pressure of carbon dioxide (43.8 +/- 4.1 vs 68.9 +/- 6.3 mm Hg, P < .01) and partial pressure of oxygen (272.3 +/- 132.7 vs 100.1 +/- 21.4 mm Hg, P < .01). ATL-146e-treated animals exhibited lower pulmonary artery pressures (33.6 +/- 2.1 vs 47.9 +/- 3.5 mm Hg, P < .01) and mean airway pressures (16.25 +/- 0.08 vs 16.64 +/- 0.15 mm Hg, P = .04). ATL-146e-treated lungs had lower wet-to-dry ratios (5.9 +/- 0.39 vs 7.3 +/- 0.38, P < .02), lower myeloperoxidase levels (2.9 x 10 -5 +/- 1.2 x 10 -5 vs 1.3 x 10 -4 +/- 4.0 x 10 -5 DeltaOD mg -1 . min -1 , P = .03), and a trend toward decreased lung tumor necrosis factor alpha levels (57 +/- 12 vs 96 +/- 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology.


CONCLUSIONS
Adenosine A 2A activation during early reperfusion attenuated lung inflammation and preserved pulmonary function in this model of lung transplantation. ATL-146e and similar compounds could play a significant role in improving outcomes of pulmonary transplantation.
Reece
T Brett
TB
Department of Surgery, University of Virginia Health System, PO Box 801359, Charlottesville, VA 22908, USA. tbr5q@virginia.edu
Ellman
Peter I
PI
Maxey
Thomas S
TS
Crosby
Ivan K
IK
Warren
Patrick S
PS
Chong
Tae W
TW
LeGallo
Robin D
RD
Linden
Joel
J
Kern
John A
JA
Tribble
Curtis G
CG
Kron
Irving L
IL
D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D001784:Blood Gas Analysis; D002245:Carbon Dioxide / Q000097:blood; D003509:Cyclohexanecarboxylic Acids / Q000276:immunology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007249:Inflammation; D008168:Lung / Q000098:blood supply* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects* / Q000276:immunology; D008297:Male; D018375:Neutrophil Activation; D009929:Organ Size; D010100:Oxygen / Q000097:blood; D009195:Peroxidase / Q000032:analysis / Q000378:metabolism; D011654:Pulmonary Edema / Q000175:diagnosis / Q000209:etiology / Q000517:prevention & control; D011687:Purines / Q000276:immunology / Q000627:therapeutic use*; D011897:Random Allocation; D043705:Receptor, Adenosine A2A / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
C431129:ATL 146e; D058908:Adenosine A2 Receptor Agonists; D003509:Cyclohexanecarboxylic Acids; D011687:Purines; D043705:Receptor, Adenosine A2A; D014409:Tumor Necrosis Factor-alpha; D002245:Carbon Dioxide; D009195:Peroxidase; D010100:Oxygen