Lung injury after cardiopulmonary bypass is attenuated by adenosine A2A receptor activation
Turner C. Lisle1, Lucas G. Fernandez1, Leo M. Gazoni1, Ashish K. Sharma1, Andrew M. Bellizzi2, Joel M. Linden3, Victor E. Laubach1, Irving L. Kron1; 1University of Virginia Department of Surgery, Charlottesville, VA; 2University of Virginia Department of Pathology, Charlottesville, VA; 3University of Virginia Department of Medicine, Charlottesville, VA
Comment on this Abstract
Objective: Cardiopulmonary bypass (CPB) has been shown to exert a systemic inflammatory response. This response, potentially mediated through the lung, can result in postoperative pulmonary dysfunction. Several studies have shown that adenosine A2A receptor (A2AR) activation attenuates lung ischemia-reperfusion injury. The effect of A2AR activation on CPB-induced lung injury has yet to be evaluated. We hypothesized that specific A2AR activation by ATL-313, an A2AR agonist, would attenuate lung inflammation following CPB.
Methods: Adult male Sprague-Dawley rats were randomly divided into three groups: 1) SHAM group (n=5), rats underwent cannulation+heparinization only; 2) BYPASS group (n=5), rats underwent 90-minutes of normothermic CPB with standard priming solution; 3) ATL group (n=5), rats underwent 90-minutes of normothermic CPB with ATL-313 (100 nM) added to the standard priming solution. Physiologic data and arterial blood gas (ABG) analysis were collected for all animals at uniform time points during the procedure. All animals were weaned from bypass without the use of ionotropes or vasopressors and allowed to recover for an additional 90-minutes. All animals were then euthanized and lung tissue, plasma, and bronchoalveolar lavage (BAL) samples were obtained for cytokine and histologic evaluation, as well as wet-to-dry lung weight ratio, a measure of pulmonary edema.
Results: ABG analysis and physiologic data were similar at all time points between groups. There was significantly less lung injury in the ATL group compared to the BYPASS group (Lung Injury Severity Score 0.8 vs. 2.2, p<0.05; Table 1). The ATL group had significant reduction in BAL IL-1, IL-6, IFN-γ and myeloperoxidase (MPO) levels compared to the BYPASS group (p<0.001 for IL-1, IL-6, and IFN-γ; p<0.05 for MPO; Table 1). Similarly, lung tissue IL-6, TNF-α, IFN-γ and pulmonary edema were significantly decreased in the ATL group compared to the BYPASS group (p<0.001 for IL-6, TNF-α, and wet-to-dry ratio; p<0.05 for IFN-γ; Table 1).
Conclusion: The addition of the A2AR agonist ATL-313 to the standard bypass priming solution prior to the initiation of CPB resulted in significantly less lung injury and pulmonary edema as well as decreased levels of several proinflammatory cytokines. ATL-313 could play an important role in reducing systemic inflammation and pulmonary dysfunction following CPB.
| Table 1 - Summary of Data |
| Lung Tissue (pg/ml) | Bronchoalveolar Lavage (pg/ml) | Wet:Dry ratio | Lung Injury Severity Score |
| Group | IL-1 | IL-6 | TNF-α | IFN-γ | MPO | IL-1 | IL-6 | TNF-α | IFN-γ | MPO |
| Sham | 10865±1086 | 403±88 | 811±90 | 1870±9 | 287946±4745 | 382±45 | 126±41 | 311±24 | 75±17 | 38700±4170 | 3.8±0.27 | 0.2±0.17 |
| Bypass | 22893±536# | 7402±371¥ | 2002±148¥ | 2530±9‡ | 302578±4091 | 753±45¥ | 389±70¥ | 330±10 | 161±17¥ | 88900±1090‡ | 7.02±0.28¥ | 2.2±0.41‡ |
| ATL | 21033±694# | 2136±247 | 765±129 | 1770±20 | 283626±5291 | 434±45 | 178±12 | 285±43 | 52±7 | 52170±3885 | 4.26±0.12 | 0.8±0.17 |
| Values are expressed as the mean±SEM. MPO-myeloperoxidase#p<0.001 vs. Sham; ¥p<0.001 vs. ATL and Sham; ‡p<0.05 vs. ATL and Sham |
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