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Ann Thorac Surg 1996;62:1494-1499
© 1996 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Relative Importance of Prostaglandin/Cyclic Adenosine Monophosphate and Nitric Oxide/Cyclic Guanosine Monophosphate Pathways in Lung Preservation

Department of Cardiothoracic Surgery, Wythenshawe Hospital, Manchester, United Kingdom

Accepted for publication June 10, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Modulation of vascular tone and platelet and neutrophil function through the prostaglandin/cyclic adenosine monophosphate or nitric oxide/cyclic guanosine monophosphate pathway can benefit lung graft function. The relative importance of these pathways is unclear.

Methods. Rat lung grafts (5 per group) were studied in an ex vivo reperfusion model. Group I grafts were pretreated with prostacyclin (20 ng•kg^-1•min^-1), flushed with cold Euro-Collins solution containing prostacyclin (200 µg/L), and reperfused immediately for 1 hour. Group II grafts were similarly procured but were stored at 4°C for 6 hours before reperfusion. In group III, no prostacyclin therapy was used; instead, the nitric oxide donor glyceryl trinitrate (0.1 mg/mL) was added to the flush/storage solution, and the grafts were stored for 6 hours.

Results. Group II grafts performed poorly compared with those in group I, with substantial deterioration of oxygenation and blood flow and elevation of pulmonary artery pressure, peak airway pressure, and wet to dry weight ratio. In contrast, graft function in group III was similar to that in controls.

Conclusions. Lung graft integrity after storage in Euro-Collins solution was better preserved by glyceryl trinitrate than by prostacyclin in this model.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Lung and heart-lung transplantation have become established as successful clinical procedures, but the numbers carried out worldwide are no longer increasing [1]. Prolonged lung preservation has been achieved in laboratory models, but clinically the incidence of early graft dysfunction has restricted available storage periods and prejudiced the distribution of scarce organs and donor-recipient matching. Early graft dysfunction with hypoxia and noncardiogenic pulmonary edema is a manifestation of ischemia-reperfusion injury and is related to inadequate preservation.

Single-flush perfusion with modified Euro-Collins (EC) solution followed by hypothermic storage is the most widely used technique of clinical lung graft procurement [2]. Concern about vasoconstriction caused by cold EC solution led to the concomitant use of prostaglandins. Prostaglandin E₁ (PGE₁) is popular in North American centers, whereas prostacyclin (PGI₂) is favored in Europe [2]. Administered to the donor before flushing or in the flush solution, their vasodilatory effect on the pulmonary vasculature is deemed to improve distribution of the flush and to confer more rapid and even cooling. These prostaglandins also have other potentially protective actions, such as inhibition of platelet aggregation and leukocyte sequestration and stabilization of membranes [3]. A beneficial effect of the use of prostaglandins in lung preservation has been demonstrated in some animal studies [4–8]. However, others have found little [9, 10] or no [11–14] such benefit.

In recent years, considerable interest has been aroused by the identification of nitric oxide (NO) as a mediator of endothelial homeostatic mechanisms. Nitric oxide is a potent vasodilator, reduces platelet aggregation and leukocyte adhesion [15], and quenches oxygen-derived free radicals [16]. The actions of NO are mediated by increasing levels of cyclic guanosine monophosphate in target cells, in contrast to PGE₁ and PGI₂, which act by increasing intracellular cyclic adenosine monophosphate.

Naka and colleagues [17, 18] have shown recently using a rat lung transplant model that lung preservation is enhanced by the addition of an NO donor, nitroglycerin (also known as glyceryl trinitrate, GTN), to the flush solution. In these studies, supplementation with GTN was compared either with no additive or with the vasodilator hydralazine. In the current study, we set out to compare directly the effects of supplementation of the NO/cyclic guanosine monophosphate and PGI₂/cyclic adenosine monophosphate pathways on pulmonary function after hypothermic storage using an isolated rat lung reperfusion model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
An ex vivo lung reperfusion model incorporating a support animal was used in these studies; it has been described in detail previously [19, 20]. All animals received humane care in compliance with the United Kingdom Government's Animals (Scientific Procedures) Act of 1986, and all procedures were carried out under terminal general anesthesia. Male Sprague-Dawley rats (Charles River Laboratories, Kent, UK) weighing 350 to 420 g were used as both lung donors and support animals. Anesthesia was induced using halothane inhalation and maintained with 100 mg/kg intraperitoneal pentobarbitone sodium. Animals and isolated grafts were ventilated using a Harvard rodent ventilator (Harvard Apparatus, Kent, UK).

Donor Procedure
Lung donors were anesthetized, intubated through a tracheostomy, and ventilated with room air. Methylprednisolone 30 mg/kg was given to all donors through the femoral vein 45 minutes before lung explantation. Median sternotomy was performed, and a ligature was passed around the aorta and main pulmonary artery.

After administration of heparin, 500 U intravenously, the inferior vena cava was clamped and the left atrial appendage was amputated. A primed, olive-tipped cannula was inserted into the pulmonary artery (PA) trunk through a ventriculotomy and secured with the previously placed ligature. The lungs were flushed through this cannula with filtered, modified EC solution precooled to 4°C and delivered by 25 cm hydrostatic pressure at a volume of 60 mL/kg. The flush time was recorded. The tracheal cannula was then clamped with the lungs fully inflated, and the heart and lungs were excised en bloc.

Donors were divided into three groups (n = 5 each). Group I and II donors were pretreated with PGI₂ (Flolan; Wellcome Foundation, London, UK) given through the inferior vena cava at a rate of 20 ng•kg^-1•min^-1 for 10 minutes immediately before flushing. Group III donors received no pretreatment. The EC flush solution (Fresenius AG, Bad Homburg, Germany) was modified by the addition of 5 mmol/L magnesium sulfate and was supplemented with PGI₂, 200 µg/L, in groups I and II and GTN (David Bull Laboratories, Warwick, UK), 0.1 mg/mL, in group III. The PGI₂ was prepared, filtered, and added just before use. Group I grafts were reperfused immediately after explantation for baseline data. Group II and III grafts were stored submerged in their respective flush solutions at 4°C for 6 hours before reperfusion.

We used PGI₂ pretreatment and addition to the flush/storage solution in the baseline group as well as in group II because the objective was to evaluate GTN supplementation against this clinically used combination. Methylprednisolone was also administered to donors (in all groups) because of its use in clinical practice.

Reperfusion
Support animals were anesthetized and ventilated with room air. Through a median sternotomy, mediastinal structures were exposed and the brachiocephalic artery was ligated. For connection to the reperfusion circuit, a cannula was inserted through the right superior vena cava and advanced through the right atrium until its tip lay in the inferior vena cava. Another cannula was passed through the left superior vena cava into the right atrium.

After removal of the left lung and postcaval lobe, the grafts were suspended in an insulated chamber and ventilated with room air using 30 cycles/min, 10 mL/kg tidal volume, and 3 cm H₂O positive end-expiratory pressure. Deoxygenated blood drawn from the inferior vena cava of the support animals was delivered into the PA of the grafts using hydrostatic pressure equivalent to the physiologic PA pressure of these rats (18 to 20 mm Hg). Graft effluent drained through the opened left atrium and was collected and returned to the right atrium of the support animals by a pump. Thus, the support animals functioned as physiologic deoxygenators. Heat losses were compensated for by water-lagging the circuit tubing and reperfusion chamber, and a warming blanket was used for the support animals. Blood obtained from a separate animal was used to prime the circuit and to replace losses together with 0.9% saline solution. All grafts were reperfused for 60 minutes.

Measurements
Gas tension and acid/base analysis was performed on blood samples taken from the reperfusion circuit proximal to the graft and from graft effluent every 5 minutes for the first 20 minutes of reperfusion, and every 10 minutes thereafter. This allowed monitoring of the stability of the support animal, consistency of (de)oxygenation of afferent blood, and reoxygenation by the graft. Graft blood flow was measured using an in-line ultrasonic flow probe (Transonic Systems, Ithaca, NY), and one of the two lumens of the reperfusion cannula was connected to a transducer for measurement of PA pressure. Flow and PA pressure were recorded and subsequently analyzed using a data aquisition package (Dataq Instruments, Akron, OH). Another transducer was used to monitor graft peak airway pressure. Lung tissue was weighed at the end of the reperfusion period and again after drying to constant weight at 120°C. Wet to dry weight ratio was calculated as (wet weight - dry weight)/dry weight.

Statistical Analysis
All data are expressed as mean ± standard error of the mean. Means were analyzed by one-way analysis of variance. If differences were found, the Bonferroni post hoc test was used to compare groups; p values less than 0.05 were considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The average flush flow rate (total flush volume/flush time) was similar in the three groups: group I, 26 ± 2 mL/min; group II, 28 ± 1 mL/min; group III, 29 ± 2 mL/min (p = not significant). All support animals remained stable during reperfusion as assessed by venous blood gas tensions and acid/base balance, core temperature, and visual inspection of the mediastinum and lungs. The partial pressure of oxygen in the graft reperfusate was constant during the experiments and within and between groups.

Reoxygenation
Grafts flushed with PGI₂ treatment and stored for 6 hours (group II) performed poorly compared with controls (Fig 1). At 1 hour, graft effluent partial pressure of oxygen was 144 ± 8 mm Hg in group I and 34 ± 8 mm Hg in group II (p < 0.001). In contrast, with the addition of GTN to the flush and storage solution (group III), oxygen tensions during reperfusion were at control levels and at 1 hour, the partial pressure of oxygen was 142 ± 4 mm Hg (p = not significant).

View larger version (22K): [in this window] [in a new window]   Fig 1. . Partial pressure of oxygen (pO2) in graft effluent during 1 hour of reperfusion. I = prostacyclin, no storage; II = prostacyclin, 6-hour storage; III = glyceryl trinitrate, 6-hour storage. Data are shown as mean ± standard error of the mean. (*p < 0.001 versus group I.)

View larger version (28K): [in this window] [in a new window]   Fig 2. . Graft blood flow during 1 hour of reperfusion. I = prostacyclin, no storage; II = prostacyclin, 6-hour storage; III = glyceryl trinitrate, 6-hour storage. Data are shown as mean ± standard error of the mean. (*p < 0.001 versus group I.)

View larger version (30K): [in this window] [in a new window]   Fig 3. . Graft mean pulmonary artery pressure (PAP) during 1 hour of reperfusion. I = prostacyclin, no storage; II = prostacyclin, 6-hour storage; III = glyceryl trinitrate, 6-hour storage. Data are shown as mean ± standard error of the mean. (*p < 0.001 versus group I.)

View larger version (24K): [in this window] [in a new window]   Fig 4. . Graft peak airway pressure (AwP) during 1 hour of reperfusion. I = prostacyclin, no storage; II = prostacyclin, 6-hour storage; III = glyceryl trinitrate, 6-hour storage. Data are shown as mean ± standard error of the mean. (*p < 0.001 versus group I.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This study has shown that after 6 hours of hypothermic storage in modified EC solution, rat lung grafts perform significantly better in terms of reoxygenation, blood flow, PA pressure, peak airway pressure, and weight gain if the flush and storage solution is supplemented with the NO donor GTN than if conventional PGI₂ treatment is used. This beneficial effect is not accompanied by improved perfusate flow rate during flush perfusion.

The rapid deterioration of function in group II is consistent with our previous experience with 6-hour rat lung preservation in EC solution [20]. Although a detrimental effect of PGI₂ on graft preservation cannot be excluded as an explanation for this deterioration, our objective was to compare GTN supplementation with current clinical practice, which frequently includes prostaglandin therapy. Further, even when EC solution is used without PGI₂, transplanted rat lung grafts fail rapidly after 6-hour storage [18].

The introduction of prostaglandins into lung graft procurement techniques resulted from concerns that reflex vasoconstriction upon administration of cold EC solution may compromise the adequacy of the flush. Pulmonary vasodilatation achieved by prostaglandins given to the donor before flushing or in the flush solution was considered to improve its distribution, wash out potentially harmful blood constituents more thoroughly, and allow more rapid and uniform cooling of the graft. Most units now include the use of PGE₁ or PGI₂ in their clinical lung harvesting procedure [2]. However, the few laboratory studies looking specifically at the effects of prostaglandins on lung preservation have not produced consistent results.

Most of these studies have used cold EC solution, with or without the addition of magnesium, for flush perfusion of lungs. In a canine heart-lung transplant model with 6-hour storage, PGI₂ pretreatment and addition to the flush solution improved survival and oxygenation [4]. Similar application of PGI₂ to in situ canine lungs flushed with cold perfusate and then subjected to 60 minutes of warm ischemia improved oxygenation, pulmonary hemodynamic indices, weight gain, neutrophil influx, and ultrastructural changes [5]. Several groups have used canine single-lung transplant models. Novick and colleagues [9] found that after 12-hour cold storage, PGI₂ pretreatment improved oxygenation but not PA pressure, airway pressure, or weight gain, whereas PGI₁ pretreatment conferred no benefit at all. With 4-hour storage and Iloprost (a PGI₂ analogue) pretreatment and addition to the flush, improvement in oxygenation and PA pressure was observed, but was only statistically significant at one time point [10]. Similar Iloprost therapy with 6 hours of storage did not benefit survival, oxygenation, or pulmonary hemodynamic indices [11]. Puskas and colleagues [12] found that donor lung hyperinflation gave better results than PGE₁ administration to the donor and flush. In a primate heart-lung transplant model, PGE₁, PGI₂, and nitroprusside pretreatment were compared; PGE₁ was found to improve ultrastructural preservation, but oxygenation was not significantly different among the groups [6]. A canine double-lung transplant model showed no benefit from PGE₁ pretreatment; in fact, survival and early gas exchange were significantly worse [13]. A recent study using a porcine single-lung transplant model found no improvement in gas exchange or pulmonary vascular resistance after the addition of PGE₁ or PGI₂ to the flush solution [14]. Two studies using Wallwork's solution for flush perfusion in isolated rat lung reperfusion models have shown the addition of PGI₂ to be beneficial [7, 8]. With no flush at all, pretreatment with PGI₂ in a canine model of in situ ischemia and reperfusion significantly improved pulmonary structure and function [21].

The conflicting results from these studies cannot be explained by differences in doses of prostaglandins used or in method of administration (ie, as pretreatment or to the perfusate). What is notable is that prostaglandin therapy does not improve the flush flow rate [10, 12], enhance cooling of the lung [9–12], or significantly alter the distribution of EC flush solution [11, 22]. This is contrary to evidence from isolated canine lobe perfusion studies, which showed that the addition of PGI₂ prevents the elevation of vascular resistance elicited by cold (4°C) EC solution [23]. On the other hand, 37°C EC solution causes vasoconstriction as well, but this is not countered by PGI₂ or PGE₁ [24]. The explanation offered by the authors of the latter study was that there are two independent triggers of vasoconstriction involved: low temperature and, at temperatures above 20°C only, high potassium concentration; prostaglandins may counter the former but not the latter. Hence in the initial phase of flush perfusion, before lung temperature falls significantly, potassium-induced, prostaglandin-resistant vasoconstriction may still occur.

Any beneficial effects of prostaglandin therapy may therefore be mediated by mechanisms other than vasodilatation. Prostacyclin is normally produced by endothelium and is known to inhibit platelet aggregation and leukocyte-endothelial interactions and to stabilize membranes [3]. Little is known about how these actions may improve the preservation of flushed lungs or attenuate reperfusion injury. It seems unlikely that exogenous prostaglandins (which have short half-lives), particularly when used for pretreatment alone, would still be available at reperfusion, during the early phase of which levels of endothelial production of PGI₂ are reduced [3]. Alteration of the behavior of any platelets and leukocytes still present in the lung after flushing or some other unidentified cytoprotective mechanism may play a role.

The other main feature of postischemic endothelial dysfunction is reduced production of NO soon after the onset of reperfusion [25, 26]. Nitric oxide has a short half-life in vivo but is a potent vasodilator, inhibits platelet aggregation and neutrophil adhesion/activation [15], and quenches oxygen-derived free radicals [16]. There is accumulating experimental evidence suggesting that interventions aimed at increasing the availability of NO during reperfusion of ischemic myocardium are protective [27, 28]. In the context of interventions at an earlier stage, enhancement of myocardial preservation by the addition of L-arginine, the precursor of endothelial NO production, before [25, 29] or during [30] ischemia has been demonstrated recently. L-arginine added to Wallwork's flush solution also improved function after 6-hour storage in an isolated rat lung reperfusion model [8]. An alternative approach to supplementing endogenous production is to use NO donors such as GTN. Although more efficient NO donors are available, such as the sydnonimine compounds [27], GTN has the advantage of already being in widespread clinical usage, and it may stimulate cyclic guanosine monophosphate production through other mechanisms as well. In a rat lung transplant model, the addition of GTN to Ringer's solution for flush perfusion was found to significantly improve survival, oxygenation, and hemodynamic indices and to reduce neutrophil sequestration during 30 minutes of reperfusion after 4 hours of hypothermic storage [17]. Similar benefit was obtained with 6-hour storage in EC solution supplemented with GTN as compared with EC alone or EC plus hydralazine [18], and also when a cyclic guanosine monophosphate analogue was added to the preservation solution [31].

Our current study has confirmed, in a different model, that supplementation with GTN during 6-hour storage in EC solution yields excellent lung graft function. Further, we have demonstrated that this is markedly more effective than the currently used clinical technique of PGI₂ administration to the donor and perfusate. The mechanism of this benefit is not yet known. Improved flush efficiency is unlikely to be the main factor in view of the similarity of perfusate flow rates between experimental groups. The conclusion of Mulvin and colleagues [7] that PGI₂ supplementation during storage is beneficial because of its vasodilatory properties was based on their finding of similar benefit with the addition of GTN, chosen as a simple vasodilator; the other NO-mediated actions of GTN had not been discerned at that time. The same questions therefore arise as to whether NO modulates the behavior of residual platelets and leukocytes in the flushed lung or preserves endothelial integrity by some other mechanism. In relation to the observed superiority of GTN over PGI₂, it may be that NO/cyclic guanosine monophosphate pathways are more important than PGI₂/cyclic adenosine monophosphate pathways in the endothelial milieu during ischemia, or that the longer half-life of GTN makes exogenous NO available for a greater proportion of the ischemic period and maybe even at reperfusion.

Further investigation of an alternative to the current practice of prostaglandin therapy in lung graft procurement is warranted. Addition of GTN to the flush solution would be simple and relatively inexpensive and would eliminate the donor systemic hypotension sometimes caused by prostaglandin pretreatment.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported by a grant from the National Heart Research Fund, United Kingdom.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Hooper, Department of Cardiothoracic Surgery, Wythenshawe Hospital, Southmoor Rd, Manchester, United Kingdom M23 9LT.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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