期刊
ANNALS OF THORACIC SURGERY
卷 95, 期 5, 页码 1762-1767出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.athoracsur.2013.01.059
关键词
-
资金
- National Institutes of Health [R01HL092953, T32HL007849]
Background. Severe ischemia-reperfusion (IR) injury leads to primary graft dysfunction after lung transplantation. Adenosine receptors modulate inflammation after IR, and the adenosine A(3) receptor (A(3)R) is expressed in lung tissue and inflammatory cells. This study tests the hypothesis that A(3)R agonism attenuates lung IR injury by a neutrophil-dependent mechanism. Methods. Wild-type and A(3)R knockout (A(3)R-/-) mice underwent 1-hour left lung ischemia followed by 2-hours reperfusion (IR). A selective A(3)R agonist, Cl-IB-MECA, was administered (100 mu g/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 A(3)R-/-mice; Cl-IB-MECA significantly decreased activation of wild-type, but not A(3)R-/-, neutrophils after acute hypoxia and reoxygenation and inhibited chemotaxis of wild-type neutrophils. Conclusions. Exogenous activation of A(3)R by Cl-IB-MECA attenuates lung dysfunction, inflammation, and neutrophil infiltration after IR in wild-type but not A(3)R-/-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 A(3)R agonists may be a novel therapeutic strategy to prevent lung IR injury and primary graft dysfunction after transplantation. (C) 2013 by The Society of Thoracic Surgeons
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