Adenosine A3 receptor activation attenuates lung ischemia-reperfusion injury.

Abstract

BACKGROUND:

Severe ischemia-reperfusion (IR) injury leads to primary graft dysfunction after lung transplantation. Adenosine receptors modulate inflammation after IR, and the adenosine A3 receptor (A3R) is expressed in lung tissue and inflammatory cells. This study tests the hypothesis that A3R agonism attenuates lung IR injury by a neutrophil-dependent mechanism.

METHODS:

Wild-type and A3R knockout (A3R-/-) mice underwent 1-hour left lung ischemia followed by 2-hours reperfusion (IR). A selective A3R agonist, Cl-IB-MECA, was administered (100 μg/kg intravenously) 5 minutes prior to ischemia. Study groups included sham, IR, and IR+Cl-IB-MECA (n = 6/group). Lung injury was assessed by measuring lung function, pulmonary edema, histopathology, and proinflammatory cytokines, and myeloperoxidase levels in bronchoalveolar lavage fluid. Parallel in vitro experiments were performed to evaluate neutrophil chemotaxis, and neutrophil activation was measured after exposure to acute hypoxia and reoxygenation.

RESULTS:

Treatment of wild-type mice with Cl-IB-MECA significantly improved lung function and decreased edema, cytokine expression, and neutrophil infiltration after IR. The Cl-IB-MECA had no effects in A3R-/- mice; Cl-IB-MECA significantly decreased activation of wild-type, but not A3R-/-, neutrophils after acute hypoxia and reoxygenation and inhibited chemotaxis of wild-type neutrophils.

CONCLUSIONS:

Exogenous activation of A3R by Cl-IB-MECA attenuates lung dysfunction, inflammation, and neutrophil infiltration after IR in wild-type but not A3R-/- mice. Results with isolated neutrophils suggest that the protective effects of Cl-IB-MECA are due, in part, to the prevention of neutrophil activation and chemotaxis. The use of A3R agonists may be a novel therapeutic strategy to prevent lung IR injury and primary graft dysfunction after transplantation.

• Authors: Daniel P Mulloy, Ashish K Sharma, Lucas G Fernandez, Yunge Zhao, Christine L Lau, Irving L Kron, Victor E Laubach
• Journal: The Annals of thoracic surgery (Ann Thorac Surg) Vol. 95 Issue 5 Pg. 1762-7 (May 2013) ISSN: 1552-6259 [Electronic] Netherlands
• PMID: 23541429 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adenosine A3 Receptor Agonists
• Receptor, Adenosine A3
• Adenosine
• 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide

Topics

• Adenosine (analogs & derivatives, therapeutic use)
• Adenosine A3 Receptor Agonists (therapeutic use)
• Animals
• Chemotaxis, Leukocyte
• Lung (blood supply)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophil Activation
• Neutrophil Infiltration (drug effects)
• Receptor, Adenosine A3 (physiology)
• Reperfusion Injury (prevention & control)