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J Thorac Cardiovasc Surg 2008;135:156-165
© 2008 The American Association for Thoracic Surgery

Cardiothoracic Transplantation

Additive protection against lung ischemia-reperfusion injury by adenosine A_2A receptor activation before procurement and during reperfusion

^a Department of Surgery, University of Virginia, Charlottesville, Va
^b Department of Pathology, University of Virginia, Charlottesville, Va
^c Medicine/Cardiovascular Research Center, University of Virginia, Charlottesville, Va.

Read at the Eighty-seventh Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5–9, 2007.

Received for publication May 4, 2007; revisions received July 20, 2007; accepted for publication August 1, 2007.

^_* Address for reprints: Leo M. Gazoni, MD, Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908. (Email: lmg2x{at}virginia.edu).

	Abstract

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Objective: Adenosine A_2A 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 A_2A 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°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 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 A_2A 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 A_2A receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A_2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A_2A receptor activation.

	Introduction

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Dr Gazoni

Although the yearly number of lung transplants worldwide has increased 130-fold over the past 20 years, critical shortages in the donor pool exist, and survivals remain low.¹ In most series, 30-day mortality rates are close to 15%, and approximately 33% of patients who receive a lung transplant die within 3 years.^2,3 Lung ischemia-reperfusion injury (LIRI) after lung transplantation continues to be one of the most common and significant causes of morbidity and mortality and has been found to increase the risk of bronchiolitis obliterans.⁴ The 30-day mortality of recipients who have reperfusion injury is as high as 40% compared with 7% in patients without graft failure.^2,4 Improvements in the care of patients with end-stage lung disease hinge on the ability to attenuate the robust inflammatory response characteristic of LIRI.

Adenosine potentially plays a critical role in minimizing ischemia-reperfusion (IR) injury inasmuch as it is known to confer protection against IR in the lungs, heart, liver, and kidney secondary to its widely described anti-inflammatory effects.^5,6 The adenosine A_2A receptor (A_2AR), one of four subtypes of the G protein–coupled adenosine receptor family that includes A₁, A_2A, A_2B, and A₃, has been associated with many anti-inflammatory properties. Adenosine receptor subclassification has shown specifically that activation of the A_2AR and resultant increases in cyclic adenosine monophosphate prevent leukocyte adhesion to endothelial cells as well as inhibiting the release of toxic oxygen products and inflammatory cytokines.^5,6 The A_2AR is predominantly expressed on inflammatory cells including neutrophils, mast cells, macrophages, monocytes, and platelets.⁷ Current evidence supports diverse mechanisms of IR injury and complex interactions between the aforementioned inflammatory cells.

Whereas the anti-inflammatory and tissue-protective effects of A_2AR activation during reperfusion are well documented, protective effects of activating the A_2AR in donor animals before transplantation have not been reported. Our group has previously shown that A_2AR activation during rabbit lung reperfusion reduces IR injury after lung transplantation.^8,9 Pretreatment of donor lung before ischemia, however, may confer better protection. Brief periods of ischemic insult before prolonged ischemia, commonly referred to as ischemic preconditioning, protect against IR injury and can be pharmacologically manipulated through activation of its key mediators.¹⁰ Growing evidence supports the emerging role of adenosine as one of these key mediators as the accumulation of adenosine from the breakdown of adenosine triphosphate is a natural method of protection against ischemia and inflammation.^11,12 In this study we examined the effect of pretreatment of donor animals with the highly selective A_2AR agonist, ATL-313, on the development of LIRI. We hypothesized that activation of A_2AR in the lung before ischemia might lead to enhanced protection compared with A_2AR activation during reperfusion alone.

	Materials and Methods

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Animal Care
New Zealand White rabbits (Burleson Enterprises, Inc, Unionville, Va) of both sexes (3.0–3.5 kg) were used for all studies and received humane care in accordance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication No.85-23, revised 1995). The Animal Care and Use Committee at the University of Virginia reviewed and approved the protocol for this study before experimentation.

Experimental Protocol
Seven experimental groups (n = 6/group, based on our most recent study¹³) were compared using an isolated, whole blood–perfused, ventilated rabbit lung model (model TIS3862; Kent Scientific, Litchfield, Conn). All groups were reperfused for 120 minutes after 18 hours of cold ischemia at 4°C (see Table 1 for the experimental protocol for each group). We used 4-(3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl)-piperidine-1-carboxylic acid methyl ester, ATL-313, a gift from Adenosine Therapeutics, LLC (Charlottesville, Va), as a potent, selective activator of the A_2AR, and 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol, ZM 241385 (Tocris, Ellisville, Mo), as a selective A_2AR antagonist. ATL-313 and ZM 241385 were dissolved in saline. Lung donors undergoing pretreatment received an intravenous injection of the drug (ATL-313 [100 nmol/L] or ATL-313 [100 nmol/L] + ZM 241385 [100 nmol/L] [note: drug concentrations are final concentrations in blood determined by calculations based on blood volume/kilogram]) 1 hour before harvest. When given during reperfusion (ATL-313 [100 nmol/L] or ATL-313 [100 nmol/L] + ZM 241385 [100 nmol/L]), the respective drugs were administered to whole blood at the beginning of reperfusion. In the group receiving ATL-313 in the lung preservation solution, the ATL-313 was added to the preservation solution at 100 nmol/L. The chosen dose of A_2AR agonists and antagonists was based on previous experiments.^14-17

Reperfusion procedure
After harvest, the lung–heart block was suspended from a force transducer and ventilation was initiated with a gas mixture of 95% oxygen and 5% carbon dioxide (model RSP1002, Kent Scientific). All groups underwent 120 minutes of whole-blood perfusion. Atelectasis was grossly eliminated by administering one breath of approximately 30 cm H₂O positive end-expiratory pressure once per minute in the first 5 minutes of the stabilization period. Lungs were ventilated at a constant tidal volume of 10 mL/kg with 3 cm H₂O of positive end-expiratory pressure at a rate of 30 breaths/min. The PA and the outflow catheters connected the lung–heart block to a venous blood reperfusion circuit. New Zealand White rabbits served as fresh venous blood donors. Blood was circulated through a pediatric oxygenator set to deoxygenate the blood and add carbon dioxide to simulate venous blood (PO ₂ = 60 mm Hg/PCO ₂ = 60 mm Hg). The lungs were subsequently perfused via the PA cannula at 60 mL/min with "venous" blood at 37°C.

Physiologic Parameters
Recordings of PA pressure and compliance were collected by a dynamic data acquisition program (DASYLab, DASYTEC, USA. Bedford, NH). Pulmonary venous blood samples were collected for blood gas analysis (Bayer 348 pH/Blood Gas Analyzer; Bayer Corp, E Walpole, Mass) at 15, 30, 60, 90, and 120 minutes after initiation of reperfusion.

Lung Wet/Dry Weight Ratio
Lung wet/dry weight ratios were used as a measure of pulmonary edema. Samples of right lower lobe lung tissue were blotted and weighed immediately after 120 minutes of reperfusion. These samples were desiccated under vacuum at 55°C until a stable dry weight was achieved.

Lung Tissue Myeloperoxidase
Myeloperoxidase (MPO) assay was performed on lung tissue to quantify neutrophil sequestration as previously described.¹⁷

Bronchoalveolar Lavage
Bronchoalveolar lavage (BAL) was performed on all lungs after the reperfusion period ended. The right upper and middle lobes were isolated and lavaged with 10 mL of normal saline. The BAL fluid was then centrifuged at 1500g for 5 minutes at 4°C. The supernatant was snap-frozen for subsequent cytokine analysis.

Enzyme-linked Immunosorbent Assay
The protein levels of tumor necrosis factor (TNF-) in BAL fluid were examined with a TNF- enzyme-linked immunosorbent assay (ELISA) purchased from BD Biosciences (San Diego, Calif) and performed according to manufacturer directions. Samples were run in triplicate.

Lung Injury Score
A blinded pathologist graded each lung sample after appropriate tissue processing and staining (hematoxylin and eosin). Each sample was graded on the basis of the number of macrophages, amount of interstitial infiltrate, and percentage of alveolae affected by fibrin deposition. Each of these three categories was then given a score of 0 to 3, resulting in a possible score ranging from 0 for uninjured lungs to 9 for the most severely injured lungs.

Statistics
Values were expressed as the mean ± standard deviation. Analysis of variance (ANOVA) was used to determine whether significant differences existed between groups. The Tukey honest significant difference multiple-comparison test was used to determine which groups were significantly different when the ANOVA results were significant. Repeated-measures analysis of variance was performed and ultimately allowed us to conclude that PA pressure, lung compliance, and oxygenation change over time and depend on group. The test for between-subject effects was significant, which implies significance in the aforementioned variables between groups.

	Results

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Physiologic Measurements
Pretreatment of donor lungs with ATL-313 and the administration of ATL-313 during reperfusion (group 5) resulted in significant decreases in PA pressure compared with all groups (P < .05) except group 4 (ATL-313, reperfusion; P = .32). No significant differences in PA pressure were observed between the administration of ATL-313 during reperfusion alone (group 4) versus ATL-313 pretreatment alone (group 2), although these interventions did result in significant decreases in PA pressure versus control (P < .01). Significant increases in lung compliance and oxygenation were observed with pretreatment of donor lungs with ATL-313 and the concurrent administration of ATL-313 during reperfusion (group 5) versus all other groups (all P < .05). The concurrent administration of ATL-313 with its antagonist, ZM 241385, nullified the physiologic effects of ATL-313 pretreatment and its administration with reperfusion. Pairwise comparisons between groups at specific time points (ie, at 15, 30, 60, 90, and 120 minutes) are found in Table 2.

ELISA for TNF-

View larger version (13K): [in this window] [in a new window]   Figure 1. BAL TNF- levels. All groups were compared with control. Lowest TNF- levels were observed in group 5. *P < .01.

View larger version (13K): [in this window] [in a new window]   Figure 2. Lung tissue MPO. All groups were compared with control. Lowest MPO activity was observed in group 5. *P < .01. OD, Optimal dose.

View larger version (13K): [in this window] [in a new window]   Figure 3. Wet/dry analysis. All groups were compared with control. Lowest wet/dry ratio was observed in group 5. *P < .01.

View larger version (115K): [in this window] [in a new window]   Figure 4. Representative hematoxylin–eosin sections of lung tissue. A, Group 5 (ATL-313 pretreatment and administration during reperfusion). B, Group 1 (control).

	Discussion

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Our study demonstrates that A_2AR activation before lung ischemia confers significant protection against the deterioration of lung function seen during reperfusion. Improved lung physiology seen with ATL-313 pretreatment correlated with significantly decreased levels of the potent proinflammatory cytokine, TNF-, pulmonary edema, neutrophil sequestration (decreased MPO), and preserved lung histology. Not surprisingly, A_2AR activation during reperfusion also provided significant protection against LIRI.^8,19 More important, clinically relevant and additive improvements in oxygenation and lung compliance were seen with the concomitant administration of ATL-313 before lung harvest and with reperfusion versus ATL-313 pretreatment alone or administration during reperfusion alone. The loss of protection observed with the administration of the A_2AR antagonist, ZM 241385, with ATL-313 indicates that the mechanism of ATL-313 protection is specifically mediated via A_2AR activation. Since A_2AR activation is known to inhibit the activation of leukocytes, the protection afforded by pretreating rabbits with ATL-313 may be due to inhibition of resident leukocytes in the transplanted lung, whereas the protection observed during reperfusion is likely due to reduced adhesion and extravasation of leukocytes in blood or reperfused lung. Of note, the temperature (4°C) of the preservation solution may account for the lack of effect of ATL-313 in this solution.

This study also highlights the emerging therapeutic role of simulating preconditioning pharmacologically by exploiting different mediators of protection. The use of adenosine and A_2AR agonists, such as ATL-313, is a logical extension of many intrinsic defense mechanisms inasmuch as adenosine is known to accumulate in response to ischemia and hypoxia.²⁰ Whereas the exact mechanisms of protection are complex and poorly understood, increased levels of adenosine before a sustained ischemic event have been shown to improve end-organ function in the liver,²¹ kidney,²² and heart,²³ although some of these effects are not mediated by A_2AR activation. Treatment with A_2AR agonists has also been associated with inhibition of inflammatory cytokine release, reduction of IR-induced apoptotic injury, and diminution of free radical production.^18,24 In an isolated, buffer-perfused rat lung model, Yildiz and colleagues²⁵ demonstrated that adenosine "preconditioning" conferred similar protection against IR-induced pulmonary vasoconstrictor dysfunction, edema, and lipid peroxidation as did their ischemic preconditioning protocol. Moreover, the administration of the nonselective adenosine receptor antagonist, theophylline, abolished the protective effects of ischemic preconditioning, thereby implying adenosine’s critical role as a mediator of preconditioning. It has not yet been determined whether a selective A_2AR antagonist such as ZM 241385 will block all of the preconditioning effects of adenosine. Nitric oxide has also been described as a protective mediator in preconditioning, decreasing LIRI with 10 minutes of nitric oxide pretreatment at 15 ppm. Limitations of the use of adenosine and nitric oxide per se as preconditioning agents are their cardiovascular side effects. Interestingly, A_2AR activation has also been associated with enhanced production of nitric oxide in cultured coronary artery cells.²⁶

The role of inflammatory cells in the pathogenesis of IR injury is unquestioned. A greater body of evidence further supports the emerging role of donor alveolar macrophages in early LIRI and its subsequent priming of other inflammatory cells such as neutrophils.²⁷ Adenosine has also been shown to decrease not only the release of TNF- and other proinflammatory cytokines from macrophages but also the activation of neutrophils from TNF- released from macrophages.²⁸ Moreover, A_2AR activation also directly interferes with neutrophil-induced IR injury. Treatment of rats with the A_2AR agonist, ATL-146e, resulted in decreased expression of the adhesion molecules P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in renal²⁹ and myocardial³⁰ IR models. A_2AR activation was shown to decrease the release of neutrophil elastase and cytokine-induced neutrophil chemoattractant, an effect that was blocked with the administration of the A_2AR antagonist, ZM 241385. Again, the administration of ATL-313 in the current study did significantly attenuate TNF- levels in BAL fluid, although the specific sources of TNF- release were not examined. Interestingly, ATL-313 pretreatment resulted in a significant decrease in the number of macrophages seen on histologic examination compared not only with control but also with the administration of ATL-313 during reperfusion alone and may account, in part, for the decreased levels of TNF- seen with pretreatment. Minimizing the quantity of macrophages may have also improved lung function by minimizing the respiratory burst activity of macrophages. Although there is indirect evidence of diminished neutrophil mediated injury with ATL-313, significant decreases in neutrophil sequestration (decreased MPO) and interstitial infiltrate seen by lung histologic studies support the anti-inflammatory properties of A_2AR activation in our model of LIRI.

Aspects of A_2AR agonism still require further elucidation. The effect of A_2AR agonism on T cells and natural killer cells, known contributors to lung IR injury, were not evaluated in this study. A_2AR agonism has, however, been observed to mitigate T cell–related interferon production and secondary macrophage activation in inflamed tissue.³¹ The immunologic effect of A_2AR agonism, especially in terms of the immunosupressed transplant patient, also requires further inquiry. A_2AR agonists may also cause systemic hypotension and thus potentially limit their clinical applicability.

The concept that IR injury is attenuated by A_2AR pretreatment and that concurrent A_2AR activation during reperfusion further improves lung function is poorly described yet clinically relevant, despite the aforementioned uncertainties. The elimination of the improvements observed with A_2AR activation with the addition of a highly selective A_2AR antagonist provides strong evidence that the mechanism of protection is specifically mediated via A_2AR activation. The specific downstream mediators of protection conferred by pharmacologic adenosine preconditioning remain elusive. Early evidence supports the activation of mitogen-activated protein kinase subtypes including extracellular signal-related kinase 1/2, jun N terminal kinase1/2, and p38 and the attenuation of apoptosis as a few of the possible mechanisms of protection conferred by adenosine receptor activation before major ischemic insult.^19,32 The pharmacologic activation of the A_2AR along with optimized timing of activation may prove to be an important therapeutic intervention in attenuating the robust inflammatory response after lung transplantation.

In conclusion, this report demonstrates that pretreatment with an A_2AR agonist protects the lung against IR injury and that further improvements in oxygenation and lung compliance occur with concurrent A_2AR activation during reperfusion. The ability to exploit and further characterize innate physiologic mechanisms of protection that minimize the contribution of inflammatory cells will likely prove to be critical in reducing the destructive consequences of LIRI and ultimately improve the care of patients with end-stage lung disease.

	Footnotes

 
Research funded by National Institutes of Health Grant RO1 HL 056093 and National Institutes of Health Training Grant 5 T32 HL007849.

¹ Drs Linden and Kron are shareholders in Adenosine Therapeutics, LLC, the corporation that provided the adenosine 2A receptor agonist ATL-313.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Victor E. Laubach Peter I. Ellman Turner C. Lisle Irving L. Kron Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gazoni, L. M. Articles by Kron, I. L. Search for Related Content PubMed Articles by Gazoni, L. M. Articles by Kron, I. L. Related Collections Related Article