Adenosine A2A receptor activation on CD4+ T lymphocytes and neutrophils attenuates lung ischemia-reperfusion injury.

Abstract

OBJECTIVE:

Adenosine A(2A) receptor activation potently attenuates lung ischemia-reperfusion injury. This study tests the hypothesis that adenosine A(2A) receptor activation attenuates ischemia-reperfusion injury by inhibiting CD4+ T cell activation and subsequent neutrophil infiltration.

METHODS:

An in vivo model of lung ischemia-reperfusion injury was used. C57BL/6 mice were assigned to either sham group (left thoracotomy) or 7 study groups that underwent ischemia-reperfusion (1 hour of left hilar occlusion plus 2 hours of reperfusion). ATL313, a selective adenosine A(2A) receptor agonist, was administered 5 minutes before reperfusion with or without antibody depletion of neutrophils or CD4+ T cells. After reperfusion, the following was measured: pulmonary function using an isolated, buffer-perfused lung system, T cell infiltration by immunohistochemistry, myeloperoxidase and proinflammatory cytokine/chemokine levels in bronchoalveolar lavage fluid, lung wet/dry weight, and microvascular permeability.

RESULTS:

ATL313 significantly improved pulmonary function and reduced edema and microvascular permeability after ischemia-reperfusion compared with control. Immunohistochemistry and myeloperoxidase content demonstrated significantly reduced infiltration of neutrophils and CD4+ T cells after ischemia-reperfusion in ATL313-treated mice. Although CD4+ T cell-depleted and neutrophil-depleted mice displayed significantly reduced lung injury, no additional protection occurred when ATL313 was administered to these mice. Expression of tumor necrosis factor-alpha, interleukin 17, KC, monocyte chemotactic protein-1, macrophage inflammatory protein-1, and RANTES were significantly reduced in neutrophil- and CD4+ T cell-depleted mice and reduced further by ATL313 only in neutrophil-depleted mice.

CONCLUSIONS:

These results demonstrate that CD4+ T cells play a key role in mediating lung inflammation after ischemia-reperfusion. ATL313 likely exerts its protective effect largely through activation of adenosine A(2A) receptors on CD4+ T cells and neutrophils.

• Authors: Ashish K Sharma, Victor E Laubach, Susan I Ramos, Yunge Zhao, George Stukenborg, Joel Linden, Irving L Kron, Zequan Yang
• Journal: The Journal of thoracic and cardiovascular surgery (J Thorac Cardiovasc Surg) Vol. 139 Issue 2 Pg. 474-82 (Feb 2010) ISSN: 1097-685X [Electronic] United States
• PMID: 19909990 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Chemical References

• ATL 313
• Adenosine A2 Receptor Agonists
• Chemokines
• Cytokines
• Piperidines

Topics

• Adenosine A2 Receptor Agonists
• Animals
• CD4-Positive T-Lymphocytes
• Capillary Permeability (drug effects, physiology)
• Chemokines (biosynthesis)
• Cytokines (biosynthesis)
• Immunohistochemistry
• Lung Diseases (prevention & control)
• Male
• Mice
• Mice, Inbred C57BL
• Neutrophil Infiltration (physiology)
• Piperidines (pharmacology)
• Reperfusion Injury (prevention & control)
• Respiratory Function Tests