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Ann Thorac Surg 1999;68:1138-1142
© 1999 The Society of Thoracic Surgeons

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Original Articles

8-Br-cGMP is superior to prostaglandin e₁ for lung preservation

^a Departments of Department of Surgery, University of Zürich Hospital, Zürich, Switzerland
^b Department of Internal Medicine, University of Zürich Hospital, Zürich, Switzerland

Address reprint requests to Dr Schmid, Division of Thoracic Surgery, University Hospital Berne, CH-3010 Berne, Switzerland

Presented at the Thirty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 25–27, 1999.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Substitution of the nitric oxide (NO) pathway reduces ischemia/reperfusion injury after lung transplantation. 8-Br-cGMP is a membrane-permeable analogue of cGMP, the second messenger of NO. In this study, we evaluated the effect of administration of 8-Br-cGMP in the flush solution on early graft function.

Methods. Unilateral left lung transplantation was performed in 10 weight-matched pairs of outbred pigs (24 to 31 kg). Donor lungs were flushed with 1.5 L cold (1°C) low potassium dextrane (LPD) solution and preserved for 20 hours. In group I (n = 5), 8-Br-cGMP (1 mg/kg) was added to the flush solution. In group II (n = 5), 8 µg/kg prostaglandin E₁ (PGE₁) was injected into the pulmonary artery (PA) before flush. One hour after reperfusion, the recipients’ contralateral right PA and bronchus were ligated to assess graft function only. cGMP levels in the PA and pulmonary vein were measured. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, and gas exchange (PaO₂) were assessed during a 5-hour observation period. Lipid peroxidation (thiobarbituric acid-reactive substance) and neutrophil migration to the allograft (myeloperoxidase activity) were measured at the end of the assessment.

Results. In group I, a significant reduction of EVLWI (group I, 6.7 ± 1.0 mL/kg vs group II, 10.1 ± 0.6 ml/kg after 2 hours of reperfusion; p = 0.022), TBARS (group I, 65.6 ± 10.0 pmol/g vs group II, 120.8 ± 7.2 pmol/g, p = 0.0039), and MPO activity (group I, 0.8 ± 0.1 change in optical density, (OD)/mg/min vs group II, 1.7 ± 0.3 OD/mg/min, p = 0.036) was noted in comparison with group II. PaO₂ levels tended to be higher in cGMP-treated animals, but the changes were not significant. Hemodynamic parameters did not differ between groups.

Conclusions. In this large animal model of lung allograft ischemia/reperfusion injury, 8-Br-cGMP as additive to the flush solution improves posttransplant lung edema, lipid peroxidation, and neutrophil migration to the allograft. This effect is not attributable to improved flush by vasodilation, as we compared 8-Br-cGMP with PGE₁ given before flush in control animals.

	Introduction

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Early graft dysfunction occurs in 10% of the recipients and is still a clinical problem in the early phase after lung transplantation [1]. Several mechanisms have been identified that mediate this type of injury including vascular dysfunction, neutrophil adhesion and migration, platelet aggregation, and oxygen free-radical production, leading to loss of endothelial barrier function and subsequent lung edema.

Substitution of the nitric oxide (NO) pathway either by direct administration of exogenous NO [2, 3] or supplementation with essential substrates of NO synthases such as L-arginine [4] or the NO-synthase cofactor tetrahydrobiopterin [5] results in improved posttransplant graft function in experimental studies representing a promising strategy to prevent posttransplant lung injury.

Ischemia and reperfusion are accompanied by a decrease of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides mediate vasodilation and play a major role in modulation of the vascular tone in the lung, as well as in the regulation of endothelial permeability and neutrophil adhesivity [6]. cAMP is a mediator of prostaglandins. Prostaglandin E₁ (PGE₁) and prostacyclin (PGI₂) are currently used in clinical lung transplantation in combination with Euro-Collins solution to improve graft preservation [1]. In this study, we evaluate the effect of 8-Bromo-cGMP, a membrane-permeable analogue of cGMP, as additive to the flush solution on posttransplant lung edema in comparison with PGE₁.

	Material and methods

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Ten weight-matched pairs of outbred pigs served as donors and recipients. Harvest and left lung transplantation were performed as previously reported [7]. The flush solution volume was 1.5 L at a temperature of 1°C. Preservation time was 20 hours at 1°C. One hour after reperfusion, the right contralateral lung was excluded from perfusion and ventilation. 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 (NIH publication 85-23, revised 1985).

Study groups
Animals were randomized into two groups. In group I (n = 5), 8-Br-cGMP (1 mg/kg; Sigma Chemicals, Buchs, Switzerland) was added to the flush solution. In group II (n = 5), 8 µg/kg PGE₁ (Prostin VR Pediatric; The Upjohn Company, Kalamazoo, MI) was injected directly into the main pulmonary artery (PA) before flush, as in clinical use.

Assessment
One hour after reperfusion of the transplanted lung, the right pulmonary arteries and the right main bronchus were ligated to assess allograft function only. During the assessment period, anesthesia was maintained with Fluothane 1.5%. FiO₂ was 100%, tidal volume was 5.5 L at a respiratory rate of 20/min and a positive end expiratory pressure (PEEP) of 5 mm H₂O. Systemic arterial, PA, central venous, and left atrial pressure were recorded continuously. Arterial and mixed venous blood were collected for gas analysis every 60 minutes. In addition, pulmonary venous and central venous blood was drawn for analysis of cGMP at the beginning of the assessment, and hourly thereafter.

At the end of the assessment period, 5 hours after reperfusion, the animals were sacrificed. Upper lobe allograft samples were submitted to histologic examination, tissue myeloperoxidase (MPO), and thiobarbituric acid-reactive substance (TBARS) assay.

Extravascular lung water
Extravascular lung water used as a direct assessment of reperfusion edema was measured as previously described [7]. A fiberoptic catheter (System Cold Z-021; Pulsion, Munich, Germany) is advanced via the external carotid artery into the descending aorta. The indicator bolus consists of two components: indocyanine green serves as intravascular marker and ice-cold 5% glucose as a thermal intravascular and extravascular indicator. The bolus is injected via the external jugular vein with a temperature-controlled injector. The dilution curves for dye and temperature are recorded simultaneously in the descending aorta with the thermistor-tipped fiberoptic catheter. Thoracic intravascular and extravascular fluid volumes are determined based on the measurement of the mean transit times for thermal and dye indicators and of the decay time volumes calculated from the indicator dilution curves as described previously [8]. The lung water computer (System Cold Z-021) determines the mean transit time for the thermal indicator and for the dye indicator, and calculates total thermal volume (ITTV), intrathoracic blood volume (ITBV), and extravascular thermal volume (ETV). The extravascular thermal volume (ETV) is calculated as follows: ETV = ITTV - ITBV. All measurements were made in triplicate. The mean value was used for analysis.

Myeloperoxidase assay
Donor and recipient lung samples were frozen immediately and stored at -80°C until assay. Quantitative MPO activity was determined using routine methods as previously described [7]. Enzyme activity is expressed as change in optical density unit per milligram of tissue protein per minute (OD/mg/min).

Thiobarbituric acid-reactive substance assay
Thiobarbituric acid-reactive substance (TBARS) levels in lung tissue were measured with 10% wet weight per volume homogenate [7]. TBARS levels were determined by reference to a standard curve of 1,1,3,3-tetramethoxy-propane (Sigma Chemicals), and the results were expressed as picomoles of malondialdehyde (MDA) per gram of wet lung.

Measurement of plasma cyclic GMP levels
Cyclic GMP concentrations were determined in pulmonary venous blood drawn from the left atrium and in peripheral venous blood drawn from the right ventricle of the recipient. Plasma was prepared and frozen at -80°C until analysis by enzyme immunoassay (EIA) (Biotrak cGMP assay; Amersham International plc, Amersham, UK) according to the manufacturer’s instructions. The detection limit of the assay used was 46 fmol/well.

Hemodynamic parameters and gas exchange
Systemic arterial, PA, central venous, and left atrial pressure were recorded continuously with a hemodynamic monitor system (Hellige, Freiburg, Germany). Measurement of cardiac output is part of the lung water assessment (System Cold Z-021, Pulsion), and the pulmonary vascular resistance was calculated in centimeter- gram-second system (CGS) units according to Poiseuille’s law. Arterial and mixed venous blood were collected for gas analysis every 60 minutes.

Statistical analysis
All values are given as the mean ± standard error of the mean (SEM). Analysis for repeated measures was performed by analysis of variance (StatView 4.5; Abacus Concepts, Inc, Berkeley, CA). p values less than 0.05 were considered significant.

	Results

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Characteristics of experimental groups
No statistical differences between groups were noted in donor weight (group I, 27.0 ± 1.6 kg vs group II, 27.1 ± 1.2 kg; p = 0.96), recipient weight (group I, 26.6 ± 1.2 kg vs group II, 27.6 ± 2.3 kg; p = 0.71), total preservation time (group I, 1,207 ± 9 minutes vs group II, 1,218 ± 16 minutes; p = 0.58), and warm ischemic time (group I, 87 ± 2 minutes vs group II, 90 ± 3 minutes; p = 0.45).

Reperfusion edema
Extravascular lung water in the allograft was significantly reduced in cGMP-treated animals (group I) compared with PGE₁-treated animals in group II (overall difference group I vs group II, p = 0.030) (Fig 1). This effect was most marked 2 hours after reperfusion (group I, 6.7 ± 1.0 mL/kg vs group II, 10.1 ± 0.6 mL/kg; p = 0.022).

View larger version (16K): [in this window] [in a new window]   Fig 1. Extravascular lung water (EVLW) in the pulmonary allograft increased in first 120 minutes after reperfusion, followed by a slight decrease in the control group. The development of posttransplant lung edema was significantly lower in the 8-Br-cGMP-treated animals (mean ± SEM).

View larger version (19K): [in this window] [in a new window]   Fig 2. PMN migration measured as MPO activity in the graft tissue shows an increase after transplantation, but remarkably less in group I. (NL = normal flushed lung tissue [mean ± SEM].)

View larger version (18K): [in this window] [in a new window]   Fig 3. Lipid peroxidation. Thiobarbituric acid reactive substance (TBARS) levels in the allograft as measurement for lipid peroxidation 5 hours after reperfusion were significantly reduced by treatment with 8-Br-cGMP (mean ± SEM).

Hemodynamic parameters and gas exchange
No significant differences were noted in hemodynamic parameters either during the 5-hour assessment period or at the end of the assessment: CO (group I, 3.3 ± 0.2 L/min vs group II, 3.1 ± 0.4 L/min; p = 0.61), PAP (group I, 36 ± 4 mm Hg vs group II, 32 ± 3 mm Hg; p = 0.27), and PVR (group I, 573 ± 67 dynes/s/cm^-5 vs group II, 580 ± 85 dynes/cm^-5; p = 0.39). PaO₂ levels tended to be higher in cGMP-treated animals, but changes were not significant (group I, 72.0 ± 5.3 kPa vs group II, 61.7 ± 7.6 kPa; p = 0.26) (Fig 4).

View larger version (15K): [in this window] [in a new window]   Fig 4. Arterial oxygenation (PaO2) over the first 5 hours. Two hours after reperfusion, PaO2 of control grafts deteriorated slowly in comparison with grafts preserved with 8-Br-cGMP, but differences were not statistically significant (mean ± SEM).

	Comment

Top Abstract Introduction Material and methods Results Comment References

In clinical practice of lung transplantation, PGE₁ is used to improve lung preservation. It is given either to the donor before flush, added to the flush solution, or given as a combination of both [9]. Prostaglandins act as pulmonary vasodilators via an increase in cAMP levels in endothelial and vascular smooth muscle cells. However, Naka and colleagues could demonstrate that vasodilation alone during lung flush is not sufficient to enhance preservation and that PGE₁ improves lung preservation by stimulating the cAMP-dependent protein kinase, which promotes nonvasodilatory mechanisms [10]. The beneficial effects of prostaglandins on lung ischemia/reperfusion injury, however, are controversial. Some investigators could demonstrate an improvement of early graft function after PGE₁ administration [11], some could not [12]. Bonser and colleagues even showed a reduced survival in comparison with control animals after 12 h of cold lung preservation and PGE₁ donor pretreatment [13].

In addition to the prostaglandin/cAMP pathway, impaired NO and cGMP production is important in the pathophysiology of lung ischemia/reperfusion injury. These mediators regulate similar functions such as vasodilation, neutrophil infiltration, and platelet aggregation. During ischemia and reperfusion, the production of both second messengers, cAMP and cGMP, is suppressed. Comparing the relative importance of both pathways, Bhabra and colleagues demonstrated in an ex vivo model of lung preservation that the failure of the NO/cGMP pathway is much more important than the failure of the prostaglandin/cAMP pathway [14].

The reduction of cGMP tissue levels during preservation may be explained by a diminished NO availability. For this decline of NO, not a loss of NO synthase activity seems to be responsible, but an accelerated formation of reactive oxygen intermediates from NO [6].

Impaired endothelium-dependent NO synthesis after ischemia and reperfusion has been observed by a number of investigators, and different strategies have been proposed for its substitution. In the lung, for example, administration of L-arginine [4] or NO donors [3] and NO inhalation [2] have been evaluated in experimental and/or clinical settings.

In a previous study, we could show that continuous administration of the essential NO synthases cofactor tetrahydrobiopterin (BH4) to the recipient during reperfusion is very effective as a physiological substitution of the impaired NO/cGMP pathway [5].

From the theoretical standpoint, L-arginine substitution does not increase NO synthesis, as intracellular L-arginine (0.8 to 2 mM) concentration is much higher than the concentration at which the reaction velocity is half maximal (2.9 µM), and the mechanism of the improvement by L-arginine remains unclear [15]. Intravascular administration of NO donors affect the systemic circulation. NO inhalation, although having the advantage of being selective for the target organ, is cumbersome for routine and prophylactic administration due to its short half-life. Furthermore, NO may react with oxygen or superoxide generated during reperfusion to form toxic peroxinitrites and other oxygen free radicals [16].

Direct and local substitution at the level of the effector messenger enables enhancement of the NO pathway during storage very effectively and may improve endothelial graft function after reperfusion. This strategy may also minimize side effects, which may play a role when substrates of an earlier step of the NO pathway are administered.

8-Br-cGMP, a lipophilic, membrane-permeable, and enzyme-resistant analogue of cGMP, has proven beneficial in reduction of ischemia/reperfusion injury in a number of experimental settings [6, 17–20].

Intravenous administration of 8-Br-cGMP, for example, resulted in inhibition of platelet accumulation in rat kidneys under conditions of ischemia/reperfusion. This effect was not related to the vasodilating properties of cGMP. Increased intracellular cGMP levels, therefore, substitute the antiplatelet activity of NO. Moreover, corresponding doses of a cAMP analogue did not have any effect on renal platelet accumulation [17]. It is known that the cGMP-mediated inhibitory effects on phospholipase C activation, inositol triphosphate generation, calcium mobilization, and also platelet activation are mediated by cGMP-dependent protein kinase [21]. Endothelial permeability is cGMP modulated by at least two mechanisms: the suppression of an increase of intracellular calcium concentration via cGMP-dependent kinase, and by elevation of the cellular cAMP concentration via the cGMP-dependent inhibition of phosphodiesterase type III. This further indicates that cGMP plays a more important role in maintenance of endothelial barrier properties than cAMP, which confirms the results of Bhabra and associates as mentioned above [14].

Naka and colleagues compared the effect of 8-Br-cGMP as an additive to the flush solution to inhaled NO in an in vivo rat model of left lung transplantation [20]. They could demonstrate that 8-Br-cGMP protected the pulmonary graft much better by reducing pulmonary vascular resistance (PVR), improving arterial oxygenation, and attenuating graft neutrophil infiltration. Chetham and associates confirmed that the cGMP analogue prevented ischemia/reperfusion-induced microvascular leak in an isolated perfused rat lung model, whereas inhaled NO could not [18]. In a recent study, addition of 8-Br-cGMP to the preservation solution resulted in improved pulmonary function in an ex vivo rabbit model [19].

In our large animal model, 8-Br-cGMP did not affect the systemic circulation of the recipient after reperfusion, which is also reflected in only sightly elevated plasma cGMP levels in the recipients in comparison with the controls. This is in accordance with previous studies, demonstrating that systemic blood pressure is not influenced by cGMP doses achieved in our experiment [22]. Furthermore, the beneficial effect of 8-Br-cGMP seems not to be attributable to improved flush by vasodilation, as we compared 8-Br-cGMP with PGE₁ given before flush in control animals, and none of the monitored hemodynamic parameters, including the pulmonary vascular resistance, changed significantly over the entire observation period.

The better graft function after cGMP administration was not accompanied by a significant improvement of gas exchange. Experimental models of posttransplant lung ischemia/reperfusion injury often use gas exchange as measurement of reperfusion injury. This parameter, however, is influenced by a variety of factors and is dependent on perfusion/ventilation distribution within the graft. Furthermore, if ischemic time of the graft in this swine model is expanded to induce a reduction of gas exchange during the assessment, the animals die within a few hours after reperfusion due to right heart failure. Moreover, the lung water computer employed in this highly reproducible model allows to assess hemodynamics and dynamic changes of pulmonary edema directly.

Euro-Collins (EC) solution is still the most commonly used preservation solution in clinical lung transplantation. We used low potassium dextrane (LPD) solution in our model, because it has proven superior for lung preservation in comparison with EC solution [23, 24] and we wanted to demonstrate the astonishing effect of 8-Br-cGMP in comparison with the best-known standard. Moreover, in this experimental setting, we are able to demonstrate that this substance is indeed improving lung preservation and is not just antagonizing the negative effects of EC solution.

In summary, we conclude that 8-Br-cGMP as an additive to the flush solution improves posttransplant lung edema, and reduces lipid peroxidation and neutrophil migration to the allograft in this large animal model. Furthermore, administration of 8-Br-cGMP to the flush is superior to clinically used PGE₁, and therefore an extremely promising strategy to enhance lung preservation and to prevent severe ischemia/reperfusion injury.

	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): Ralph A. Schmid Walter Weder Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hillinger, S. Articles by Weder, W. Search for Related Content PubMed PubMed Citation Articles by Hillinger, S. Articles by Weder, W.