Attenuation of Pulmonary Ischemia-Reperfusion Injury by Adenosine A2B Receptor Antagonism.
BACKGROUND
Ischemia-reperfusion injury (IRI) is a major source of morbidity and mortality after lung transplantation. We previously demonstrated a proinflammatory role of adenosine A2B receptor (A2BR) in lung IR injury. The current study tests the hypothesis that A2BR antagonism is protective of ischemic lungs after in vivo reperfusion or ex vivo lung perfusion (EVLP).


METHODS
Mice underwent lung IR with or without administration of ATL802, a selective A2BR antagonist. A murine model of EVLP was also used to evaluate rehabilitation of donation after circulatory death (DCD) lungs. DCD lungs underwent ischemia, cold preservation, and EVLP with Steen solution with or without ATL802. A549 human type 2 alveolar epithelial cells were exposed to hypoxia-reoxygenation (HR) (3 hours/1 hour) with or without ATL802 treatment. Cytokines were measured in bronchoalveolar lavage (BAL) fluid and culture media by enzyme-linked immunoassay (ELISA).


RESULTS
After IR, ATL802 treatment significantly improved lung function (increased pulmonary compliance and reduced airway resistance and pulmonary artery pressure) and significantly attenuated proinflammatory cytokine production, neutrophil infiltration, vascular permeability, and edema. ATL802 also significantly improved the function of DCD lungs after EVLP (increased compliance and reduced pulmonary artery pressure). After HR, A549 cells exhibited robust production of interleukin (IL)-8, a potent neutrophil chemokine, which was significantly attenuated by ATL802.


CONCLUSIONS
These results demonstrate that A2BR antagonism attenuates lung IRI and augments reconditioning of DCD lungs by EVLP. The protective effects of ATL802 may involve targeting A2BRs on alveolar epithelial cells to prevent IL-8 production. A2BR may be a novel therapeutic target for mitigating IRI to increase the success of lung transplantation.
Department of Surgery, University of Virginia, Charlottesville, VA.
Mary E
ME
Huerter
Department of Surgery, University of Virginia, Charlottesville, VA.
Ashish K
AK
Sharma
Department of Surgery, University of Virginia, Charlottesville, VA.
Yunge
Y
Zhao
Department of Surgery, University of Virginia, Charlottesville, VA.
Eric J
EJ
Charles
Department of Surgery, University of Virginia, Charlottesville, VA.
Irving L
IL
Kron
Department of Surgery, University of Virginia, Charlottesville, VA.
Victor E
VE
Laubach
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D008168:Lung / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*
D058917:Adenosine A2 Receptor Antagonists; D016207:Cytokines