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J Thorac Cardiovasc Surg 2005;129:1137-1143
© 2005 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Adenosine A_2A receptor activation reduces inflammation and preserves pulmonary function in an in vivo model of lung transplantation

^a Department of Surgery, University of Virginia Health System, Charlottesville, Va
^b Department of Pathology, University of Virginia Health System, Charlottesville, Va
^c Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Va

Read at the Thirtieth Annual Meeting of The Western Thoracic Surgical Association, Maui, Hawaii, June 23–26, 2004.

Received for publication June 21, 2004; revisions received October 15, 2004; accepted for publication November 17, 2004.

^_* Address for reprints: T. Brett Reece, MD, University of Virginia Health System, Department of Surgery, PO Box 801359, Charlottesville, VA 22908 (E-mail: tbr5q{at}virginia.edu).

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 µg 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 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 OD mg^–1 · min^–1, P = .03), and a trend toward decreased lung tumor necrosis factor levels (57 ± 12 vs 96 ± 15 pg/mL, P = .06). The ATL group demonstrated significantly less inflammation on histology.

CONCLUSION: 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.

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