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J Thorac Cardiovasc Surg 2002;124:973-978
© 2002 The American Association for Thoracic Surgery

Cardiothoracic Transplantation (TX)

Adenosine A_2A receptor activation decreases reperfusion injury associated with high-flow reperfusion

From the Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Charlottesville, Va.

Supported by the National Institutes of Health (NIH) under R01 grant HL56093-03, National Research Service Award F32 grant HL10248-01, and cooperative agreement U54 HD28934 as part of the Specialized Cooperative Centers Program in Reproduction Research.

Read at the Eighty-first Annual Meeting of The American Association for Thoracic Surgery, San Diego, Calif, May 6-9, 2001.

Received for publication May 15, 2001. Revisions requested June 28, 2001; revisions received Dec 27, 2001; revisions requested Feb 13, 2002; revisions received Feb 18, 2002. Accepted for publication Feb 21, 2002. Address for reprints: Steven M. Fiser, MD, Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, PO Box 801359, MR4 Building, Room 3111, Charlottesville, VA 22908 (E-mail: smf9e{at}virginia.edu).

	Abstract

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Introduction: High pulmonary artery flow rates can result in severe reperfusion injury after lung transplantation. Our hypothesis was that selective activation of the adenosine A_2A receptor with a highly specific analog (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion.
Methods: Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Measurements of pulmonary artery pressure (in millimeters of mercury), arterial oxygenation (in millimeters of mercury), myeloperoxidase, peak inspiratory pressure, and wet/dry weight ratio were obtained. Groups 1 (high flow) and 2 (high flow ATL-146e) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL-146e) underwent controlled reperfusion with an initial reperfusion of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 µg · kg^-1 · min^-1.
Results: ATL-146e significantly improved lung physiologic measurements under both high-flow (group 1 vs group 2) and controlled high-flow (group 3 vs group 4) conditions after 30 minutes.
Conclusions: The adenosine A_2A receptor analogue ATL-146e significantly decreases the severity of reperfusion injury in the setting of both high-flow and controlled high-flow reperfusion.

	Introduction

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Despite improvements in lung transplantation, transplanted lungs remain vulnerable to ischemia-reperfusion injury, with severe graft dysfunction occurring in 20% of lung transplant recipients. ^1,2 Although severe graft dysfunction can be reversible, it is often associated with the need for prolonged intensive care and increased mortality. ^3,4 It has become increasingly evident that reperfusion is responsible for the majority of tissue injury after lung transplantation. ⁵ Additionally, some investigators have suggested that high pulmonary artery flow rates increase the risk of severe reperfusion injury after lung transplantation. In our clinical practice, patients with preexisting pulmonary hypertension are at increased risk for reperfusion injury. ⁶ Other authors have also shown that a more severe reperfusion injury seems to occur in these patients as well. ^7-9 The increased risk for reperfusion injury in these patients might be the result of activation of the inflammatory cascade against endothelium that is damaged as a result of the high-flow state. Our hypothesis was that selective activation of the adenosine A_2A receptor with a highly specific analogue (ATL-146e) would inhibit leukocyte activation and decrease reperfusion injury after high-flow reperfusion.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Experimental protocol
Using our isolated, ventilated, blood-perfused rabbit lung model, all groups (n = 8 per group) underwent lung harvest, 4 hours of cold storage, and blood reperfusion for 30 minutes. Groups 1 (high flow) and 2 (high flow ATL) underwent reperfusion at 120 mL/min for 30 minutes. Groups 3 (controlled high flow) and 4 (controlled high flow ATL) underwent controlled reperfusion with an initial reperfusion rate of 60 mL/min for the first 5 minutes, followed by a rate of 120 mL/min for 25 minutes. During reperfusion, groups 2 and 4 received ATL-146e at 4 µg · kg^-1 · min^-1. This dose was selected after a preliminary experiment with doses of ATL-146e at 0.01, 0.1, 1.0, and 4.0 µg · kg^-1 · min^-1.

Harvest procedure
Adult New Zealand White rabbits of both sexes weighing 3.0 to 3.5 kg were randomly assigned to the 3 experimental groups. Animals were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (5 mg/kg). Tracheal intubation was performed through a tracheostomy, and mechanical ventilation was instituted with a constant pressure ventilator (#RSP1002; Kent Scientific Corp, Litchfield, Conn) with room air at a rate of 18 breaths/min. A median sternotomy and thymectomy were then performed. The 2 superior and 1 inferior venae cavae were loosely encircled with ligatures, and the pericardium was opened. Both the pulmonary artery (PA) and aorta were dissected free and similarly encircled. A purse-string suture was placed in the free wall of the right ventricle, and intravenous heparin was administered (500 U/kg). After injection of 30 µg of alprostadil (prostaglandin E₁; Upjohn Company, Kalamazoo, Mich) into the PA, the cavae were interrupted, and onset of ischemia was noted. The PA was then cannulated through a right ventriculotomy placed in the center of the purse-string suture. Both the right ventricle and PA ligatures were tied to secure the cannula. After venting the left ventricle with a left ventriculotomy and ligating the aorta, 50 mL/kg Euro-Collins (Hamburg, Germany) preservation solution was infused at 4°C into the PA from a height of 30 cm. Topical cooling was achieved with cold saline solution slush. During the PA flush, the left atrium was cannulated through the left ventriculotomy with an outflow catheter and a catheter to directly transduce left atrial pressures. A purse-string suture was placed to secure these cannulas. After completion of the PA flush, the inflow and outflow cannulas were clamped. The heart-lung block was then excised, and the tracheostomy tube was clamped at end inspiration. The inflated lungs were stored immersed in saline solution at 4°C for 4 hours. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals," published by the National Institutes of Health (National Institutes of Health publication No. 85-23, revised 1996).

Reperfusion procedure
After organ harvest and ischemic storage, the heart-lung block was suspended in a warm, humidified tissue chamber, and ventilation was reestablished with a 95% oxygen and 5% carbon dioxide gas mixture at a respiratory rate of 18 breaths/min by using the constant pressure ventilator (Figure 1). The inflow and outflow cannulas were then connected to a venous blood reperfusion circuit. New Zealand White rabbits weighing 3.5 to 5.0 kg served as fresh venous blood donors. The lungs were reperfused with venous blood from a main reservoir. A second nonrecirculated venous blood reservoir was used to challenge the lungs and to determine the single-pass oxygenation values during reperfusion. The circuit (Kent Scientific Corp) was designed to recirculate 150 mL of warmed blood with a roller pump (#7521-40; Cole Palmer Instrument Co, Chicago, Ill).

View larger version (20K): [in this window] [in a new window]   Fig. 1. Isolated, blood-perfused rabbit lung model: diagram of the isolated lung model. P, Pressure transducer; N2, nitrogen gas; O2, oxygen gas.

Lung wet/dry weight ratios
Lung wet/dry weight ratios were used as a measurement of pulmonary edema. Samples of lung tissue were weighed immediately after reperfusion. These samples then underwent passive desiccation at room temperature until a stable dry weight was achieved. The weight immediately after reperfusion and the stable dry weight were then used to calculate the lung wet/dry weight ratios.

Lung tissue myeloperoxidase
A myeloperoxidase assay was performed to quantify neutrophil sequestration. Lung tissue was placed in 5 mL of 0.5% hexadecyltrimethyl-ammonium bromide in 50 mmol/L potassium phosphate solution (pH 7.4) and disrupted by means of homogenizing at 4°C. The solution was centrifuged at 15,000g for 15 minutes at 4°C, and the supernatant was discarded. The pellet was resuspended in 2 mL of 0.5% hexadecyltrimethyl-ammonium bromide in 50 mmol/L potassium phosphate solution (pH 6.0) and homogenized. Tissue was disrupted further by means of ultrasonication and 3 freeze-thaw cycles (liquid nitrogen bath/37°C water bath). The solution was again centrifuged at 15,000g for 15 minutes at 4°C. Aliquots (0.1 mL) of supernatant were added to the assay buffer of o-dianisdine dihydrochloride, H₂O₂, and 50 mmol/L potassium phosphate (pH 6.0). Absorbance at 460 nm was measured over 2 minutes by means of spectrophotometry (LKB Model 4050, Cambridge, England). Lung tissue myeloperoxidase activity was expressed as the change in absorbance per milligram of dry weight per minute.

Statistical analysis
Statistical analysis was performed by using analysis of variance on SPSS software (SPSS Inc, Chicago, Ill). Significant differences were determined by using the Tukey significant difference test. Data are expressed as means ± SD.

	Results

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Physiologic measurements
The high-flow ATL group (73.4 ± 22.0 mm Hg, P = .002, Figure 2) had significantly improved arterial oxygenation measurements compared with those of the high-flow group (41.0 ± 11.7 mm Hg) after 30 minutes of reperfusion. Similarly, the controlled high-flow ATL group (123.6 ± 19.7 mm Hg, P = .004) had significantly improved arterial oxygenation measurements compared with those of the high-flow group (87.0 ± 27.5 mm Hg) after 30 minutes of reperfusion.

View larger version (18K): [in this window] [in a new window]   Fig. 2. Arterial oxygenation. The high-flow ATL group (High-ATL) had significantly improved arterial oxygenation after 30 minutes of reperfusion compared with that of the high-flow (High) group. Similarly, the controlled high-flow ATL (CP-ATL) group had significantly improved arterial oxygenation compared with that of the controlled high-flow (CP) group. *P = .002, high-flow ATL group versus high-flow group; **P = .004, controlled high-flow group ATL versus controlled high-flow group.

View larger version (13K): [in this window] [in a new window]   Fig. 3. Pulmonary artery pressure. The high-flow ATL group (High-ATL) had a significantly lower PAP compared with that of the high-flow (High) group. Similarly, the controlled high-flow ATL (CP-ATL) group had significantly improved PAP measurements compared with those of the controlled high-flow (CP) group. *P < .015, high-flow ATL group versus high-flow group; **P < .003, controlled high-flow ATL group versus controlled high-flow group.

Lung wet/dry weight ratio
The wet/dry weight ratio was significantly lower in the high-flow ATL group (11.8 ± 1.28, P = .018) compared with that in the high-flow group (13.7 ± 1.62). Wet/dry weight ratio was not significantly different between the controlled high-flow ATL group (6.0 ± 1.49, P = .184) and the controlled high-flow group (6.9 ± 1.01).

Tissue myeloperoxidase assay
Myeloperoxidase activity was not significantly different between the high-flow (0.31 ± 0.09 absorbance/mg dry weight/min) and high-flow ATL groups (0.29 ± 0.09 absorbance/mg dry weight/min). Similarly, myeloperoxidase activity was not significantly different between the controlled high-flow (0.22 ± 0.08 absorbance/mg dry weight/min) and controlled high-flow ATL (0.17 ± 0.06 absorbance/mg dry weight/min) groups.

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Approximately 20% to 30% of all lung transplant recipients experience reperfusion injury, which has an associated mortality of 40% in some series. ^1,2 Although the exact mechanism of this process has not been fully discerned, clinical studies have suggested that certain patient populations, such as patients with preexisting pulmonary hypertension, might be at increased risk for reperfusion injury after lung transplantation. ^7-9 In our own clinical practice, patients with preexisting pulmonary hypertension are at increased risk of reperfusion injury. ⁶ A more severe reperfusion injury seems to occur in patients with preexisting pulmonary hypertension as well. ^7-9 This patient population would include patients with primary pulmonary hypertension in addition to patients with secondary pulmonary hypertension as a result of congenital heart defects. Additionally, however, patients undergoing lung transplantation for restrictive lung diseases often have severe pulmonary hypertension as a result of pulmonary fibrosis. Other authors, in addition to the present ones, have shown an increased risk of reperfusion injury in patients with restrictive lung disease. ^6,10

One possible mechanism by which those patients have reperfusion injury is through mechanical disruption of the pulmonary vascular endothelium. This would result in increased pulmonary edema and lung dysfunction as a result of the disrupted endothelium. Another possible mechanism for the increased reperfusion injury seen in those patients is through increased hydrostatic gradient created by increased PAP, which might serve to drive fluid across endothelial membranes. Additionally, endothelial disruption results in collagen exposure, which might be serving to activate circulating leukocytes against the transplanted lung. Many studies have shown that circulating white blood cells are one of the major mediators of reperfusion injury after lung transplantation. ^11-15

One of the major anti-inflammatory mechanisms used by endothelial cells is mediated through the release of adenosine. ² Adenosine receptors are ubiquitous membrane receptors found on many inflammatory cell types, including macrophages and neutrophils. ^16-20 Activation of these receptors results in suppression of the inflammatory function of these cells. Adenosine has been shown to be a protective agent in models of warm lung ischemia-reperfusion injury, ²¹ cardiac ischemia-reperfusion injury, ²² intestinal reperfusion injury, ²³ and hepatic ischemia-reperfusion injury. ²⁴ Different types of adenosine receptors exist (A₁, A_2A, A_2B, and A₃) and have different functions. For example, the adenosine A₁ receptor can have proinflammatory effects, including neutrophil chemotaxis and neutrophil adherence to endothelial cells. ²² To avoid these proinflammatory effects, we chose a selective A_2A receptor analogue. Adenosine receptor subclassification has shown specifically that activation of the adenosine A_2A receptor prevents leukocyte adhesion to endothelial cells, as well as inhibiting the release of toxic oxygen products. ¹⁷

The present study demonstrates that leukocyte inhibition with ATL-146, which is a highly potent and specific activator of the adenosine A_2A receptor, ²⁵ results in improved arterial oxygenation and PAP under both high-flow and controlled high-flow reperfusion conditions. Additionally, pulmonary edema, as assessed on the basis of wet/dry weight ratio, was significantly lower in the high-flow ATL group compared with in the high-flow group. These data would suggest that the inflammatory cascade has a role in reperfusion injury after high-flow reperfusion.

Interestingly, although myeloperoxidase activity was lower in the high-flow ATL group compared with that in the high-flow group and in the controlled perfusion ATL group compared with that in the controlled perfusion group, these comparisons did not reach statistical significance. Had the experiment been carried out for a longer time period, the gradual buildup of sequestered leukocytes might have brought out more of a difference between the various groups. Another possibility, however, is that the adenosine analogue is acting on cells other than circulating leukocytes. Previously, we have shown that circulating leukocytes are not significantly involved in reperfusion injury until after 2 hours of reperfusion. ¹⁵ Furthermore, our studies have also suggested that intrinsic pulmonary macrophages might be involved in the earliest phase of reperfusion injury after lung transplantation. ²⁶ Alveolar macrophages, in addition to circulating neutrophils, are known to carry the A_2A receptor and thus might be the initial key target for the A_2A analogue. Another possibility is that the A_2A analogue was acting directly on the pulmonary vasculature, leading to vasodilation, although many studies have shown the action of this drug is on white blood cells. ^16-20

One further observation in this study was the effect of controlled perfusion on reperfusion injury. Controlled perfusion seemed to improve physiologic measurements compared with high-flow reperfusion. Our group has previously published on this topic. ²⁷

In summary, high-flow reperfusion can cause significant lung dysfunction after lung transplantation. Adenosine A_2A receptor activation with ATL-146e significantly reduces reperfusion injury associated with high-flow and controlled high-flow conditions, possibly by inhibiting white blood cells. Thus adenosine A_2A agonists might have a future clinical role in lung transplantation.

	Appendix: Discussion

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Dr Ralph A. Schmid (Berne, Switzerland). Why did you use the Euro-Collins solution in these experiments? I think the era of Euro-Collins is over.

Dr Fiser. We still use Euro-Collins at our institution.

Dr Schmid. Did you look at reperfusion for longer times than 30 minutes? This is a very short observation time, and therefore the differences might not be significant.

Dr Fiser. No, we only looked at 30 minutes. I think our future studies involving high-flow reperfusion should be carried out for more extended time periods.

	Acknowledgments

 
We thank Anthony Herring and Sheila Hammond for their expert technical advice and support.

	References

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 

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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 Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Curtis G. Tribble Aditya K. Kaza John A. Kern Irving L. Kron Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fiser, S. M. Articles by Kron, I. L. Search for Related Content PubMed PubMed Citation Articles by Fiser, S. M. Articles by Kron, I. L. Related Collections Lung - transplantation Lung - basic science