Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury

Lucas G. Fernandez, Ashish K. Sharma, Damien J. Lapar, Irving L. Kron, Victor E. Laubach

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Objectives: Ischemia-reperfusion injury contributes significantly to morbidity and mortality in lung transplant patients. Currently, no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury by binding to various adenosine receptors; however, the role of the adenosine A1 receptor in ischemia-reperfusion injury and inflammation is not well understood. The present study tested the hypothesis that selective, exogenous activation of the A1 receptor would be anti-inflammatory and attenuate lung ischemia-reperfusion injury. Methods: Wild-type and A1 receptor knockout mice underwent 1 hour of left lung ischemia and 2 hours of reperfusion using an in vivo hilar clamp model. An A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance, and pulmonary artery pressure. The wet/dry weight ratio was used to assess edema. The myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine the presence of neutrophil infiltration and inflammation. Results: In the wild-type mice, 2-chloro-N6-cyclopentyladenosine significantly improved lung function and attenuated edema, cytokine expression, and myeloperoxidase levels compared with the vehicle-treated mice after ischemia-reperfusion. The incidence of lung ischemia-reperfusion injury was similar in the A1 receptor knockout and wild-type mice; and 2-chloro-N6-cyclopentyladenosine had no effects in the A1 receptor knockout mice. In vitro treatment of neutrophils with 2-chloro-N6-cyclopentyladenosine significantly reduced chemotaxis. Conclusions: Exogenous A1 receptor activation improves lung function and decreases inflammation, edema, and neutrophil chemotaxis after ischemia and reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia-reperfusion injury after transplantation.

Original languageEnglish (US)
Pages (from-to)1654-1659
Number of pages6
JournalJournal of Thoracic and Cardiovascular Surgery
Volume145
Issue number6
DOIs
StatePublished - Jun 2013
Externally publishedYes

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine

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