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Updated: Jul 8, 2026
Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury
Published on: April 12, 2024
Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement
Leo M Gazoni1, Victor E Laubach, Daniel P Mulloy
1Department of Surgery, University of Virginia, Charlottesville 22908, USA. lmg2x@virginia.edu
Objective:
Adenosine A2A receptor activation during reperfusion improves lung ischemia-reperfusion injury. In this study we sought to determine whether pretreatment of rabbits with a potent and selective adenosine A2A receptor agonist, ATL-313, before transplantation or whether adding ATL-313 to the preservation solution results in equivalent or additional protection compared with ATL-313 added during reperfusion.
Methods:
An isolated, ventilated, ex vivo blood-perfused rabbit lung model was used. All groups underwent 2 hours of reperfusion after 18 hours of cold ischemia (4 degrees C). ATL-313 was administered 1 hour before ischemia intravenously, with the preservation solution, and/or during reperfusion.
Results:
Both pretreatment of donor animals with ATL-313 or adding ATL-313 just during reperfusion improved pulmonary function, but significantly greater improvement was observed when pretreatment and treatment during reperfusion were combined (all P < .05). Myeloperoxidase levels, bronchoalveolar lavage tumor necrosis factor alpha levels, and pulmonary edema were all maximally decreased in the combined treatment group. The administration of an equimolar amount of the potent and highly selective adenosine 2A receptor antagonist, ZM 241385, along with ATL-313, resulted in the loss of protection conferred by ATL-313.
Conclusions:
Adenosine A2A receptor activation with ATL-313 results in the greatest protection against lung ischemia-reperfusion injury when given before ischemia and during reperfusion. Improved pulmonary function observed with adenosine A2A receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor alpha and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A2A receptor activation.
Insights
Administering adenosine A2A receptor agonist ATL-313 before ischemia and during reperfusion offers the greatest protection against lung ischemia-reperfusion injury. This combined approach significantly reduces inflammation and edema, improving lung function.
Area of Science:
- Cardiovascular and Respiratory Physiology
- Transplantation Immunology
- Pharmacology
Background:
- Lung ischemia-reperfusion injury (IRI) is a major complication in lung transplantation.
- Adenosine A2A receptor activation has shown promise in mitigating IRI.
Purpose of the Study:
- To evaluate the efficacy of ATL-313, a selective adenosine A2A receptor agonist, in preventing lung IRI.
- To compare the protective effects of ATL-313 administered before ischemia, during reperfusion, or in combination.
Main Methods:
- An ex vivo blood-perfused rabbit lung model was utilized.
- ATL-313 was administered intravenously before ischemia, in the preservation solution, and/or during reperfusion.
- Lung function, myeloperoxidase levels, tumor necrosis factor alpha, and pulmonary edema were assessed.
Main Results:
- Both pretreatment and reperfusion treatment with ATL-313 improved pulmonary function.
- Combined pretreatment and reperfusion treatment yielded significantly greater protection than either alone.
- The protective effects were abolished by the adenosine A2A receptor antagonist ZM 241385.
Conclusions:
- Combined administration of ATL-313 before ischemia and during reperfusion provides maximal protection against lung IRI.
- ATL-313's protective mechanism is specifically mediated through adenosine A2A receptor activation.
- Improved lung function correlates with reduced inflammatory markers and edema.
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