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Ann Thorac Surg 1997;63:339-344
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Low-Dose Nitric Oxide Inhalation During Initial Reperfusion Enhances Rat Lung Graft Function

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

Accepted for publication September 4, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. In ischemia-reperfusion injury, the production of nitric oxide by dysfunctional endothelium falls rapidly within minutes of the onset of reperfusion. Replenishment during this critical early period using inhaled nitric oxide may benefit lung grafts through modulation of vascular tone, endothelial permeability, neutrophil and platelet function, and availability of reactive oxygen species.

Methods. Rat lung grafts were flushed with 60 mL/kg cold University of Wisconsin solution and were reperfused either immediately (group I, n = 5) or after 24-hour 4°C storage (groups II and III, n = 5 each), for 60 minutes in an ex vivo model incorporating a support animal. Graft ventilation was with room air. In group III, 20 parts per million inhaled nitric oxide was added during the initial 10 minutes of reperfusion, whereas in groups I and II, equivalent flows of nitrogen were added to standardize oxygen concentration.

Results. Compared with group I, graft function in group II was poor, with reductions in oxygenation and blood flow and elevations of mean pulmonary artery pressure, peak airway pressure, and wet to dry weight ratio. In contrast, during nitric oxide inhalation in group III, graft function improved to control levels. This improvement was subsequently sustained throughout the reperfusion period.

Conclusions. Low-dose inhaled nitric oxide administration in the early phase of reperfusion of stored lung grafts can yield sustained improvement in function. There may be a role for inhaled nitric oxide in the prevention of reperfusion injury in transplanted lungs.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The importance of the active role of the vascular endothelium in homeostatic mechanisms has become increasingly evident in recent years. In addition to its permeability barrier function, the endothelium produces locally acting substances such as nitric oxide (NO), prostacyclin, and adenosine, which mediate vasodilatation and inhibit platelet aggregation and leukocyte adherence [1]. In ischemia-reperfusion (IR) injury, endothelial dysfunction with reduced production of these protective agents and increased expression of adhesion molecules appears to be critical. This dysfunction is triggered by a burst of oxygen-derived radicals generated at reperfusion, with a subsequent rapid fall in available NO levels [2–4]. Exogenous NO supplementation may therefore prevent the progression of IR injury through vasodilatation, inhibition of platelet aggregation and leukocyte adherence to endothelium [2, 5], reduction of protein leakage [5, 6], and scavenging of reactive oxygen species [7]. This prevention has been achieved in animal models of myocardial IR injury using either L-arginine (the precursor of endogenous NO production) or NO donors [8, 9]. The use of the latter has been necessary because NO itself reacts rapidly with hemoglobin and so has a short half-life in vivo.

In the lung, on the other hand, it is possible to administer NO directly by inhalation. Inhaled NO is already used clinically as a vasodilator in the treatment of patients with increased pulmonary vascular resistance [10]. This method of delivery can improve ventilation-perfusion matching by increasing blood flow selectively in well-ventilated parts of the lung, unlike vasodilators given systemically. Further, as NO is inactivated by blood, systemic hypotension is minimized. In this context, inhaled NO also has been used in the treatment of lung transplant recipients with established graft dysfunction, with successful reversal of pulmonary hypertension and hypoxemia [11, 12].

We hypothesized that rather than using inhaled NO in this way to treat established lung graft reperfusion injury, it may be possible to prevent development of the injury by administering it during initial reperfusion. Previous studies in which this has been attempted have produced mixed results [13, 14], and a possible toxic effect of NO has been suggested, involving reactions with superoxide with production of peroxynitrite and hydroxyl radicals. However, in these studies, relatively high doses of inhaled NO were used. Further, high inspired oxygen fractions were used with no monitoring of levels of nitrogen dioxide, a toxic product generated rapidly when NO mixes with oxygen. Using a model in which rat lung grafts are reperfused with blood from a support animal, we administered low-dose (20 ppm) inhaled NO, in room air, during only the initial 10 minutes of reperfusion of grafts stored for 24 hours in cold University of Wisconsin solution. We ensured that nitrogen dioxide levels remained low during NO delivery and assessed graft function during a total of 1 hour of reperfusion.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All animals in this study 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 lung donors and support animals. Anesthesia was induced with halothane and maintained with intraperitoneal pentobarbitone sodium, 100 mg/kg. Harvard rodent ventilators (Harvard Apparatus, Kent, UK) were used for animal and isolated graft ventilation.

Graft Procurement
Lung donors were ventilated through a tracheostomy with room air using 60 breaths/min, 10 mL/kg tidal volume, and 3 cm H₂O positive end-expiratory pressure. Methylprednisolone 30 mg/kg was given through the femoral vein 45 minutes before lung explantation, in keeping with clinical practice. Median sternotomy was performed, and the pleurae and pericardium were opened. After administering 500 U of heparin, we occluded the inferior vena cava and excised the left atrial appendage. The lungs were then flushed with 60 mL/kg 4°C University of Wisconsin solution (DuPont Pharmaceuticals, Letchworth Garden City, UK), delivered through a cannula placed in the pulmonary artery (PA), using 25 cm hydrostatic pressure. The heart-lung block was excised with the lungs fully inflated and was submerged in flush solution for storage.

Reperfusion
Grafts were suspended in a warmed chamber after excision of the left lung and postcaval lobe and were reperfused for 1 hour with deoxygenated blood from a support animal (Fig 1), as described previously [15]. The support animals were cannulated through a median sternotomy. A 16-gauge intravenous cannula was passed through the right superior vena cava and right atrium into the inferior vena cava. Blood drawn through this cannula was delivered hydrostatically into the PA of the grafts. Delivery was achieved by placing the grafts below the support animals, with the vertical distance between the two being sufficient to generate hydrostatic reperfusion pressure equivalent to the physiologic PA pressure of this species (18 to 20 mm Hg). Graft effluent draining from the opened left atrium was collected and returned by a pump (Variable Speed Peristaltic Pump; Harvard Apparatus) to the right atrium of the support animal through an 18-gauge cannula placed through the left superior vena cava. Thus, the support animals functioned as deoxygenators. The circuit tubing and reperfusion chamber were water-lagged to maintain blood temperature at 38°C, and support animals were placed on a warming blanket (Harvard Apparatus). Blood obtained from additional animals (1 donor per one or two experiments) and 0.9% saline solution were used to prime the circuit and to replace losses.

View larger version (17K): [in this window] [in a new window]   Fig 1. . Reperfusion apparatus. Deoxygenated blood drawn from the inferior vena cava (IVC) of the support animal is delivered to the graft by hydrostatic pressure, generated by a height differential (H) between the two. Graft effluent is returned by a pump (P) to the right atrium (RA) of the support animal. (F = flowmeter; T = pressure transducer; V = ventilator.)

Experimental Protocol
Fifteen grafts were harvested and were assigned to one of three groups (n = 5 per group). Group I grafts were reperfused immediately after explantation for baseline data. Group II and III grafts were stored for 24 hours submerged in 4°C University of Wisconsin solution before reperfusion. In group III, 20 ppm inhaled NO was administered during the first 10 minutes of reperfusion. This reduced the inspired oxygen fraction from 0.21 to 0.20. Therefore, in groups I and II, the NO delivery system was used to add nitrogen alone at a rate that achieved the same reduction in inspired oxygen fraction during the initial 10 minutes of reperfusion. For the remaining 50 minutes of reperfusion, ventilation was with room air only in all groups.

Measurements
Concentrations of inspired NO, nitrogen dioxide, and oxygen were monitored as described earlier. Blood samples were taken at intervals from the graft effluent for measurement of partial pressure of oxygen (PO₂). Graft blood flow was measured using an in-line ultrasonic flow probe (Transonic Systems, Ithaca, NY), while one of the two lumens of the reperfusion cannula was connected to a transducer for measurement of graft mean PA pressure. The grafts were reperfused using physiologic hydrostatic pressure, but the actual (measured) PA pressure varied according to the pulmonary vascular resistance and was also affected by airway pressures. A data-aquisition package (Dataq Instruments, Akron, OH) was used to record and subsequently analyze flow and PA pressures. The graft ventilator was linked to another transducer for measurement of peak airway pressure. Grafts were weighed after termination of reperfusion and again after drying to constant weight at 120°C for calculation of wet-to-dry weight ratios.

During reperfusion, the stability of the support animals was assessed by monitoring core temperature, heart rate, degree of filling of the heart and great vessels, and acid-base and gas tension analysis of venous blood sampled from the reperfusion circuit. The latter also allowed monitoring of graft reperfusate PO₂.

Statistical Analysis
Data are expressed as mean ± standard error of the mean. Group means of final measurements were compared by one-way analysis of variance. If differences were found, the Bonferroni post hoc test was used for significance testing; p values less than 0.05 were considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
All experiments were technically successful, and the support animals remained stable. The core temperature and acid-base status of the support animals and PO₂ of the graft reperfusate (Fig 2) did not vary significantly during the experiments or within or between groups. In group III, during inhaled NO administration, final concentrations of NO were maintained between 19 and 21 ppm. Nitrogen dioxide concentrations did not exceed 1 ppm. Measured inspired oxygen fraction in all groups was 0.20 during the first 10 minutes of reperfusion and 0.21 subsequently.

View larger version (13K): [in this window] [in a new window]   Fig 2. . Partial pressure of oxygen (pO2) in the graft reperfusate over the reperfusion period. There were no statistical differences between groups or within groups over time. Data are shown as mean ± standard error of the mean.

View larger version (14K): [in this window] [in a new window]   Fig 3. . Partial pressure of oxygen (pO2) in the graft effluent during 1 hour of reperfusion of grafts flushed with University of Wisconsin solution and reperfused immediately (group I) or after 24-hour storage (groups II and III). Group III received 20 ppm inhaled nitric oxide for the first 10 minutes of reperfusion. Data are shown as mean ± standard error of the mean. (***p < 0.001 versus group I.)

View larger version (18K): [in this window] [in a new window]   Fig 4. . Blood flow during 1 hour of reperfusion of grafts flushed with University of Wisconsin solution and reperfused immediately (group I) or after 24-hour storage (groups II and III). Group III received 20 ppm inhaled nitric oxide for the first 10 minutes of reperfusion. Data are shown as mean ± standard error of the mean. (***p < 0.001 versus group I.)

View larger version (17K): [in this window] [in a new window]   Fig 5. . Mean pulmonary artery pressure (MPA) during 1 hour of reperfusion of grafts flushed with University of Wisconsin solution and reperfused immediately (group I) or after 24-hour storage (groups II and III). Group III received 20 ppm inhaled nitric oxide for the first 10 minutes of reperfusion. Data are shown as mean ± standard error of the mean. (**p < 0.01 versus group I.)

View larger version (13K): [in this window] [in a new window]   Fig 6. . Peak airway pressure (AWP) during 1 hour of reperfusion of grafts flushed with University of Wisconsin solution and reperfused immediately (group I) or after 24-hour storage (groups II and III). Group III received 20 ppm inhaled nitric oxide for the first 10 minutes of reperfusion. Data are shown as mean ± standard error of the mean. (*p < 0.05 versus group I.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
In this study, we hypothesized that supplementation of NO during the initial phase of reperfusion of stored lung grafts may prevent the progression of IR injury. Inhaled NO at 20 ppm was administered during the first 10 minutes of reperfusion of rat lungs after 24-hour hypothermic storage in University of Wisconsin solution. Nitrogen dioxide levels were monitored to ensure that they did not exceed 1 ppm. Whereas untreated stored grafts performed poorly in terms of oxygenation, blood flow, PA pressure, peak airway pressure, and weight gain (the latter reflecting edema, cellular infiltration, and hemorrhage), those receiving inhaled NO functioned at control levels throughout the reperfusion period.

Nitric oxide is a relatively simple molecule with a short biological half-life, but has an array of effects [16]. It acts through stimulation of production of cyclic guanosine monophosphate in target cells [10]. It is a potent vasodilator, and it inhibits platelet aggregation and adherence of neutrophils to endothelium. Evidence for a deficiency in endothelial NO production during IR injury comes from studies of isolated artery rings. Vasomotor responses in these rings dependent on endothelial NO production have been shown to be diminished within minutes of the onset of reperfusion of ischemic myocardium [2]. Similar endothelial dysfunction occurs in reperfused lungs. Hence, NO-mediated responses in canine lungs were normal after 3-hour cold storage but were impaired after subsequent reperfusion for 1 hour [17]. In a rabbit lung model, such responses were unaltered after up to 48 hours of hypothermic storage, but were significantly reduced after 5-hour storage and 4 hours of reperfusion [18]. Direct measurements of NO have shown rapid decreases in levels during reperfusion of ischemic myocardium [3] and hypothermically stored lungs [4]. Deficiency of NO may contribute to the development of IR injury, and it follows that exogenous supplementation may be beneficial.

This concept is supported by the majority of studies in which myocardial NO availability has been modulated during IR. Inhibition of NO synthesis has been shown to potentiate IR injury, whereas administration of the NO precursor L-arginine, or substances that donate NO, during myocardial ischemia and/or reperfusion can attenuate injury [8, 9]. Some studies, on the other hand, have shown that inhibition of NO synthesis can also be protective in myocardial IR injury, suggesting that NO can have deleterious effects too [19].

The importance of the NO pathway in pulmonary preservation also is becoming apparent. Improved function has been demonstrated in lung grafts stored in solutions supplemented with nitroglycerin (an NO donor) [20, 21] or cyclic guanosine monophosphate analogues [4, 13]. We have shown recently that sustained improvement of rat lung graft function can be achieved by administration of nitroglycerin during the first 10 minutes of reperfusion [22]. However, high doses were required. Unlike other organs, it is possible in lungs to administer gaseous NO during reperfusion. Inhaled NO is already used clinically as a selective pulmonary vasodilator [10]. It diffuses from the alveoli and activates pulmonary vascular smooth muscle cyclic guanosine monophosphate, thereby inducing relaxation. Any NO reaching the vascular lumen is rapidly inactivated by binding to hemoglobin. Hence, two of the major unwanted side effects of conventional vasodilators are avoided: systemic hypotension and increased shunting of blood through poorly ventilated parts of the lung. Successful treatment of increased pulmonary vascular resistance and hypoxemia by inhaled NO has been reported in lung transplant recipients with life-threatening graft dysfunction [11, 12].

Previous experimental use of inhaled NO during initial lung graft reperfusion, however, has not been uniformly successful. Naka and colleagues [13] performed lung transplantation in rats after 6-hour hypothermic storage in EuroCollins solution and administered 65 ppm inhaled NO throughout the reperfusion period. Four of 12 grafts functioned well, but the remainder failed rapidly. In comparison, all untreated grafts failed, whereas those supplemented with a cyclic guanosine monophosphate analogue during storage performed well. Eppinger and colleagues [14] subjected rat lungs to 90 minutes of warm in situ ischemia. Administration of 80 ppm inhaled NO during reperfusion resulted in increased endothelial permeability to albumin at 30 minutes, whereas some improvement was seen after 4 hours. The apparently toxic effect of NO demonstrated in these reports, as well as in studies of myocardial IR injury [19], is generally attributed to the reaction of NO with superoxide, with the production of cytotoxic peroxynitrite and hydroxyl radicals. Tissue levels of the enzyme xanthine oxidase and of one of its substrates, hypoxanthine, build up during ischemia; when oxygen, the other substrate, is introduced at reperfusion, rapid, short-lived generation of superoxide occurs [23]. Eppinger and colleagues [14] were able to prevent the increase in lung injury associated with NO administration in their model by blocking superoxide formation, as well as by delaying NO treatment for 10 minutes, thereby avoiding its interaction with the early burst of superoxide.

Formation of peroxynitrite from NO and superoxide occurs at a rate that depends on the product of their concentrations [23]. Thus, a small increase in the level of either can greatly increase peroxynitrite formation. There is evidence that oxygen-derived free-radical production in postischemic lungs increases with the concentration of oxygen used for ventilation during reperfusion [24]. Naka and associates [13] and Eppinger and colleagues [14] used oxygen and NO concentrations of 70%/65 ppm and 60%/80 ppm, respectively. Consequently, the levels of production of peroxynitrite and hydroxyl radicals in their models may have been high. Further, the combination of these concentrations of gases in the ventilatory mixture may have produced toxic amounts of nitrogen dioxide, which is converted by water into nitric acid and peroxynitrite [10]. It is not clear in either study what precautions were taken to avoid nitrogen dioxide formation or whether its levels were monitored.

In the current study, these potential problems were avoided by using lower concentrations of NO and oxygen and by ensuring that nitrogen dioxide formation was minimal. Further, NO delivery was restricted to a short initial period of reperfusion because logically, this is when supplementation is most likely to be successful in preventing IR injury. Using this strategy, we were able to demonstrate a clear, sustained improvement in graft function. It is not known as yet what the precise mechanism of this protection was. Vasodilatation may play a major role. We have shown previously that reducing the initial reperfusion pressure is in itself beneficial to graft function [15]. Inhaled NO can lower pulmonary capillary pressure sufficiently to reduce albumin leakage in injured lungs [6]. On the other hand, we have also found that administering the direct vasodilator hydralazine during initial reperfusion is only partially beneficial [22], and so the other protective actions of NO may be equally important. Neutrophil involvement in tissue destruction during IR injury is facilitated by adherence to dysfunctional endothelium, and it has been shown that this adherence can be prevented by NO donors [5]. Increased endothelial permeability to protein is similarly diminished by NO donors [5]. Nitric oxide can also inhibit the production of superoxide by neutrophils [25] and can scavenge oxygen-derived free radicals [7]. Although we cannot from our results identify the relative importance of these various mechanisms, it is clear that provision of supplemental NO during only the first 10 minutes of reperfusion effectively prevented progression of reperfusion injury, such that subsequent function remained excellent. The fact that termination of NO administration in group III was not followed by any increase in PA pressure (see Fig 5) suggests that endothelial function in terms of the production of endogenous vasorelaxants had returned to normal by this time.

Although in our previous studies, we have demonstrated similar success in ameliorating lung graft reperfusion injury using nitroglycerin as an NO donor [22], inhaled NO therapy is much more attractive because of its other advantages, namely the avoidance of systemic hypotension and improvement of ventilation-perfusion matching. The dose used in this study was relatively low [6, 11–14], but evidence is accumulating that even lower doses can be effective in acute lung injury, with concomitant reduction in the risk of toxicity [26]. Using low oxygen concentrations, however, is not possible in lung transplant recipients, and so before inhaled NO can be considered as a prophylactic measure in graft reperfusion, further studies are required to establish optimal, safe combinations of the two gases.

	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 M23 9LT, United Kingdom.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract 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): David N. Hopkinson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bhabra, M. S. Articles by Hooper, T. L. Search for Related Content PubMed PubMed Citation Articles by Bhabra, M. S. Articles by Hooper, T. L.