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Ann Thorac Surg 1996;62:1639-1643
© 1996 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Inhaled Nitric Oxide Reveals and Attenuates Endothelial Dysfunction After Lung Transplantation

Lars Lindberg, MD, Per Ola Kimblad, MD, PhD, Trygve Sjöberg, PhD, Richard Ingemansson, MD, PhD, Stig Steen, MD, PhD

Departments of Cardiothoracic Surgery and Anesthesiology and Intensive Care, University Hospital of Lund, Lund, Sweden

Accepted for publication July 22, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Maintaining endothelial function within transplanted organs may be critical to successful preservation. In this study we have evaluated the relationship between the effect of inhalation of nitric oxide and the degree of endothelial dysfunction after lung transplantation.

Methods. A left lung, which had been preserved for 24 hours, was transplanted and a right pneumonectomy was performed in 5 pigs. After a 24-hour observation period the pigs inhaled 5, 20, and 80 ppm nitric oxide, and pulmonary vascular resistance was recorded continuously. From the same donors preserved pulmonary arteries from the contralateral lung were studied simultaneously in organ baths. Acetylcholine chloride was used to elicit endothelium-dependent relaxation in vessel segments contracted with the thromboxane A2 analogue U-46619.

Results. Maximal endothelium-dependent relaxation decreased in the preserved lungs and correlated to the pulmonary vascular resistance in the simultaneously transplanted lungs. Inhalation of nitric oxide in the pigs that had received transplants caused the pulmonary vessels to dilate in proportion to the endothelial dysfunction.

Conclusions. Preservation of lung for transplantation induces an endothelial dysfunction, and the degree of the decrease in pulmonary vascular resistance caused by nitric oxide inhalation may be an indication of the degree of this endothelial damage. The vasodilation caused by inhaled nitric oxide increases as the endothelial function deteriorates.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
In 1980, Furchgott and Zawadzki described that the relaxing effect of acetylcholine on smooth muscle cells was endothelium-dependent, and in 1987 two independent groups identified this "endothelium-derived relaxing factor" as nitric oxide (NO) or a related compound [1, 2]. These discoveries revealed that the vascular endothelium is an important regulatory organ; it has been shown to modulate vascular smooth muscle tone and mediate hemostasis, cellular proliferation, inflammatory mechanisms, and immune mechanisms in the vessel wall.

In lung transplantation, preservation of the endothelium is important, because poor preservation of the endothelium might lead to vasoconstriction, occlusion, and intimal hyperplasia. Exposure of subendothelial structures would increase the risk of graft rejection [3]. This emphasizes the need for good endothelial preservation, but it also raises possibilities of mitigating the effects of endothelial injury by administering endothelium-derived relaxing factors postoperatively. Nitric oxide, being an endothelium-derived relaxing factor and easily administrable to the lungs through inhalation, may therefore be a good complement to a deficient endogenous production of NO.

The aim of this study was to compare the response of pulmonary vascular resistance to inhalation of NO and the endothelium-dependent relaxation in a porcine lung transplantation model.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Ten pigs (5 donors and 5 recipients) of a native Swedish breed and with a mean weight of 56 kg were used. All of the animals received human 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). A schematic diagram of the experimental protocol is shown in Figure 1Go.



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  		Fig 1. . Experimental protocol. After flush perfusion and 24 hours of cold (6° to 8°C) storage, ring segments were taken from an intralobar pulmonary artery for studies in organ baths, simultaneously with a left lung transplantation for hemodynamic studies. (NO = nitric oxide; PVR = pulmonary vascular resistance.)

 
Anesthesia
Anesthesia was induced with intramuscular ketamine (Ketalar; Parke-Davis, Morris Plains, NJ), 30 mg/kg body weight. Sodium thiopental (Pentothal; Abbot, North Chicago, IL), 100 to 200 mg, and atropine (Pharmacia, Uppsala, Sweden), 1 mg, were given intravenously before tracheostomy (tube no. 7). Anesthesia was maintained with a continuous infusion of 30 mL/h of a solution containing 8 g (16 mg/mL) ketamine, 300 mg (0.6 mg/mL) pancuronium (Pavulon; Organon Teknika, Boxtel, the Netherlands), and 30 mg (0.06 mg/mL) midazolam (Dormicum; Roche, Basel, Switzerland) in 500 mL of 10% glucose. A Servo-Ventilator 300 (Siemens-Elema AB, Solna, Sweden) was used for mechanical ventilation, and identical settings were used in all pigs during the NO inhalation: volume-controlled pressure-regulated ventilation, 10 L/min, 20 breaths/min, with an inspired oxygen fraction of 0.21 and a positive end-expiratory pressure of 8 cm H2O.

Donor Procedure
A median sternotomy was performed. After systemic heparinization (4 mg/kg), the pulmonary artery was perfused with 8 L of Perfadex solution (Medisan Pharmaceuticals AB, Uppsala, Sweden) at room temperature (20° to 23°C), and the perfusion pressure was kept between 10 and 20 mm Hg. The surgical technique and the composition of the solutions have been described in detail previously [4]. After perfusion, the lungs were excised in a collapsed state. The left lung and one segment of the right lung were immersed in cold (6° to 8°C) Perfadex for 24 hours (see Fig 1Go).

Recipient Procedure
After anesthesia had been induced as outlined above, catheters were placed in the right internal jugular vein and in the right carotid artery. The above-mentioned left lung, after being preserved for 24 hours, was transplanted, immediately followed by pneumonectomy of the contralateral lung. A Swan-Ganz catheter (right ventricular ejection fraction/volumetric oximetry thermodilution catheter 93A-750H-7.5F; Baxter Healthcare Corp, Santa Ana, CA) was inserted through the right external jugular vein and flow-directed into the pulmonary artery. The catheter was connected to an Edwards Critical-Care Explorer Multiple Parameters Hemodynamic Monitor (Baxter Healthcare Corp). A catheter was inserted into the left atrium for pressure measurements, and an ultrasonic bloodflow probe (14 mm) was placed around the pulmonary artery. After ventilatory support and observation for 24 hours the pigs inhaled NO at an inspired oxygen fraction of 0.21.

Nitric Oxide Delivery
A gas cylinder (AGA AB, Lidingö, Sweden) with 10,000 ppm NO in nitrogen was used to administer 5, 20, and 80 ppm NO for 8 to 10 minutes. Nitric oxide was delivered into the inspiratory limb of the breathing circuit of the ventilator by a microprocessor-governed valve. The system provides a precision of ±10% of the set value when tested with a chemiluminescence analyzer (Model 952A; Beckman Instruments Inc, Process Instruments & Controls Groups, Fullerton, CA).

Hemodynamic Measurements
Electrocardiogram; systemic, mean, and diastolic arterial pressures; central venous pressure; systemic, mean, and diastolic pulmonary arterial pressures; and left atrial pressure were monitored continuously with Hewlett-Packard fluoroscopes (HP78353B and HP78342B; Andover, MA). Blood flow was monitored continuously on a Transonic Flowmeter T201D (Transonic Systems Inc, Ithaca, NY). Pressures and analog signals from the blood flow meter were collected on a computer supplied with a data acquisition system (Viewdac; Keithley, Rochester, NY). Pulmonary vascular resistance and systemic vascular resistance were computed continuously from the pressures and blood flow. Signals were sampled 50 times per second, and the mean values were displayed on a monitor every fifth second and saved on the computer hard disk.

Recording of Endothelium-Dependent Relaxation
From the segment of the right lung that had been preserved for 24 hours, a branch of an intralobar pulmonary artery was dissected free from surrounding tissues with a dissecting microscope (Leika Wild M 691; Wild Leitz Ltd, Heerbrugg, Switzerland). The vessel segments were approximately 1 mm in external diameter and 2.0 mm long according to a graticule. The segments were immersed in temperature-controlled (37°C) organ baths containing 5 mL of Krebs solution, continuously bubbled with a mixture of 95% O2 and 5% CO2, giving a pH of approximately 7.40 (Krebs solution contains [in mmol/L]: NaCl, 119; NaHCO3, 15; KCl, 4.6; NaH2PO4, 1.2; MgCl2, 1.2; CaCl2, 1.5; and glucose, 11). Each ring segment was suspended between two metal holders (0.2 mm in diameter), of which one was attached to a Grass FT O3C transducer connected to a Grass polygraph for continuous recording of isometric tension. The other metal holder was attached to an adjustable unit by which the vessel segments were repeatedly stretched until a basal tension of about 4 mN was reached after an equilibration period of approximately 2 hours. In previous experiments maximum response was obtained at this tension in ring segments of similar size from the pulmonary artery of the pig. Contraction was induced in the vessel segments with the thromboxane A2-mimic U-46619 (Upjohn, Kalamazoo, MI) at 10-6.5 mol/L. When the contraction had reached steady state, acetylcholine (Sigma, St Louis, MO) was added cumulatively (10-9 to 10-3 mol/L) to induce endothelium-dependent relaxation, and the maximal relaxation, expressed as a percentage of the contraction induced by U-46619, was determined.

Data Analysis
The maximum endothelium-dependent relaxation obtained with acetylcholine was plotted for each animal together with the decrease in pulmonary vascular resistance to inhalation of NO, and regression analyses were performed with the "least squares" method to check for a correlation between the in vitro and in vivo data.

The response of pulmonary vascular resistance to inhalation of NO was analyzed. Curve fittings were performed in Statistica for Windows (Statsoft Inc, Tulsa, OK) with the quasi-Newton method. The start of the function was set to be the first value that was followed by at least two additional consecutive values where the pulmonary vascular resistance decreased.

A p value of less than 0.05 was considered statistically significant. All data are expressed as the mean ± the standard error of the mean.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Pulmonary vascular resistance curves for each pig obtained during inhalation of 5, 20, and 80 ppm NO are shown in Figure 2Go. With the start of NO inhalation, pulmonary vascular resistance declines in two distinct phases, which best fit a biexponential function. The first phase has a half-life of 9.6 ± 3.0, 4.2 ± 0.5, and 3.6 ± 0.8 seconds during inhalation of 5, 20, and 80 ppm NO, respectively. The second phase, which becomes obvious after completion of the rapid wash-in phase, is slower and has a half-life of 2.88 ± 0.6, 1.75 ± 0.4, and 2.26 ± 0.4 minutes during inhalation of 5, 20, and 80 ppm NO, respectively. There are no significant differences in half-lives between different doses of NO during either the first or the second phase. The mean duration needed to decrease pulmonary vascular resistance by 95% in this pig model, regardless of NO dose given, is 9.81 ± 1.18 minutes.



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  		Fig 2. . Pulmonary vascular resistance (PVR) response for individual pigs during inhalation of 5, 20, and 80 ppm nitric oxide (NO). The curve for each pig is indicated by the same symbol in the different panels.

 
There were no significant changes in arterial oxygen tension during NO inhalation regardless of dose given. The mean arterial oxygen tension was 7.6 ± 0.6, 7.9 ± 0.7, and 7.5 ± 0.7 mm Hg before, during, and after NO inhalation, respectively (inspired oxygen fraction of 0.21).

Linear regression analysis showed a correlation between maximum endothelium-dependent relaxation and pulmonary vascular resistance before inhalation of NO (p = 0.021) (Fig 3Go). Maximum endothelium-dependent relaxation was also correlated to the decrease in pulmonary vascular resistance on inhalation of NO at 5 ppm (p = 0.01) and 80 ppm (p = 0.04), but did not reach statistical significance at 20 ppm (p = 0.08) (Fig 4Go).



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  		Fig 3. . Results of regression analysis performed to check for correlation between the maximum endothelium-dependent relaxation and pulmonary vascular resistance (PVR) after lung transplantation. (NO = nitric oxide.)

 


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  		Fig 4. . Results of regression analysis performed to check for correlation between the maximum endothelium-dependent relaxation and the decrease in pulmonary vascular resistance (PVR) during nitric oxide (NO) inhalation after lung transplantation.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
We have developed a method by which the link between preservation, clinical signs, and endothelium-dependent relaxation can be evaluated [4]. We earlier found a decrease in maximum endothelium-dependent relaxation in donor lungs after preservation/storage for transplantation, which was correlated to an increase in pulmonary vascular resistance after transplantation [5]. The findings of an impaired endothelium-dependent vasorelaxation and an unaltered endothelium-independent vascular smooth muscle relaxation after lung transplantation [6] strongly suggest that it is mainly the endothelium of the pulmonary vessels that is impaired in lung preservation. This is in agreement with findings in hearts after ischemia and reperfusion [7]. It also indicates that the endothelium may be the most vulnerable and therefore the most important structure to preserve in transplantation.

In this study we have found a correlation between the decrease in pulmonary vascular resistance during NO inhalation and an impaired endothelium-dependent relaxation. Pulmonary vasodilatation during NO inhalation increases concurrently with a decrease in endothelium-dependent relaxation. This relationship indicates a possibility of indirectly estimating the extent of the endothelial injury by analyzing the response to inhalation of NO.

Nitric oxide has been reported to play an important role in leukocyte-endothelium interaction [8]. It decreases cytokine-induced endothelial expression of adhesion molecules [9] by its role as a free radical scavenger [10]. In lung transplantation, supplementation of the preservation solution with the NO donor nitroglycerin has been shown to reduce neutrophil infiltration [11], and NO inhalation has also been shown to decrease leukocyte sequestration in the lungs during extracorporeal circulation in pigs [12]. Exogenous NO, delivered either intravenously as a precursor or as an inhalation, may thus protect the transplanted lung against leukocytes and thereby improve capillary flow and perhaps reduce the risk of graft rejection.

Single-lung transplantation for pulmonary hypertension is especially prone to posttransplantation pulmonary edema. Nitric oxide modulates microvascular permeability [13], and inhaled NO has been shown to decrease pulmonary transvascular albumin flux in patients with acute lung injury [14]. In a rat model of single-lung transplantation, inhaled NO effectively reduced pulmonary edema [15].

The ischemia-reperfusion injury associated with preservation of organs for transplantation may be due to free oxygen radicals [16]. The location of the endothelium makes it especially susceptible to oxidant injury, which occurs mainly at the level of the plasma membrane, where a number of ion transport pathways are affected [17]. Nitric oxide donors have been shown to protect endothelium from these oxidative injuries [18].

It has been hypothesized that NO might be deleterious because NO and superoxide radicals during reperfusion theoretically could liberate peroxynitrite and hydroxyl radical, but this has not been verified [19]. On the contrary, inhalation of NO has been reported to be beneficial after lung transplantation [20, 21].

The potential production of nitrogen dioxide during NO inhalation is probably of more concern. Its toxic effects have been investigated in both animal and human studies, and even at doses of 5 ppm nitrogen dioxide or less, detrimental effects on diffusion capacity, oxygenation, airway resistance, cilia function, and pulmonary defense against microorganisms have been reported [22–24]. The upper safety limit of 5 ppm nitrogen dioxide set by the Occupational Safety and Health Administration seems, therefore, to be too high, especially in patients with pulmonary diseases, who probably are more sensitive to further injuries and infections. Therefore, inhalation of NO demands careful monitoring of nitrogen dioxide levels in the inhaled gas. It must also be emphasized that the concentration of inhaled NO and oxygen should be adjusted to a minimal level as long as nitrogen dioxide cannot be scavenged effectively [25].

The response of pulmonary vascular resistance to inhalation of NO was biphasic and fit a biexponential curve. The first phase, when pulmonary vascular resistance decreases rapidly, represents the wash-in of NO, and an almost instant response to NO indicates that the pulmonary vascular smooth muscle is viable and active. The second, slower phase most probably represents a redistribution of NO within the lung. The inhaled gas is redistributed from "fast" alveoli with low compliance or low airway resistance to "slow" alveoli with high compliance or high airway resistance. Because "slow" alveoli are ventilated less, they contain a high partial pressure of carbon dioxide and a concomitantly low partial pressure of oxygen. "Fast" ventilated alveoli and lung units are the first to be exposed to inhaled gas, and NO will therefore dilate vessels to these alveoli first and improve arterial oxygenation. If the concentration of inhaled NO is high enough to reach the "slow" hypercarbic and hypoxic alveoli before it is inactivated, it will dilate the vessels to these alveoli, ie, inhibit hypoxic pulmonary vasoconstriction, increase ventilation/perfusion mismatch, and decrease arterial oxygenation. This explains why higher concentrations of inhaled NO may decrease arterial oxygenation but still decrease pulmonary vascular resistance, and this is in agreement with the findings by Gerlach and associates [26]. A long gas distribution time may also increase the oxidation of NO, but the rate of intrapulmonary conversion of NO to nitrogen dioxide and the significance of this is still unknown.

In conclusion, preservation of lungs for transplantation induces an endothelial dysfunction that may have clinical importance. The magnitude of the decrease in pulmonary vascular resistance caused by inhalation of NO seems to be an indication of the degree of endothelial injury.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
This study was supported by grants from the Swedish Heart Lung Foundation, Westerströms Foundation, and the Medical Faculty, University of Lund.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address reprint requests to Dr Steen, Department of Cardiothoracic Surgery, University Hospital of Lund, S-221 85 Lund, Sweden.


   References
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524–6.[Medline]
  2. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265–9.[Abstract/Free Full Text]
  3. Ryan US. The endothelial cell surface and response to injury. Fed Proc 1986;45:101–8.[Medline]
  4. Steen S, Kimblad P, Sjöberg T, Lindberg L, Ingemansson R, Massa G. Safe lung preservation for twenty-four hours with Perfadex. Ann Thorac Surg 1994;57:450–7.[Abstract]
  5. Kimblad P, Sjöberg T, Steen S. Pulmonary vascular resistance related to endothelial function after lung transplantation. Ann Thorac Surg 1994;58:416–20.[Abstract]
  6. Kimblad PO, Massa G, Sjöberg T, Steen S. Endothelium-dependent relaxation in pulmonary arteries after lung preservation and transplantation. Ann Thorac Surg 1993;56:1329–33.[Abstract]
  7. Seccombe JF, Schaff HV. Coronary artery endothelial function after myocardial ischemia and reperfusion. Ann Thorac Surg 1995;60:778–88.[Abstract/Free Full Text]
  8. Kanwar S, Kubes P. Nitric oxide is an antiadhesive molecule for leukocytes. New Horiz 1995;3:93–104.[Medline]
  9. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60–8.
  10. Gaboury JP, Woodman RC, Granger DN, Reinhardt PH, Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol 1993;265:H862–7.[Abstract/Free Full Text]
  11. Naka Y, Chowdhury NC, Oz MC, et al. Nitroglycerin maintains graft vascular homeostasis and enhances preservation in an orthotopic rat lung transplant model. J Thorac Cardiovasc Surg 1995;109:206–11.[Abstract/Free Full Text]
  12. Malmros C, Blomquist S, Dahm P, Mårtensson L, Thörne J. Nitric oxide inhalation decreases pulmonary platelet and neutrophil sequestration during extracorporeal circulation in the pig. Crit Care Med 1996;24:845–9.[Medline]
  13. Kubes P, Granger DN. Nitric oxide modulates microvascular permeability. Am J Physiol 1992;262:H611–5.[Abstract/Free Full Text]
  14. Benzing A, Brautigam P, Geiger K, Loop T, Beyer U, Moser E. Inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury. Anesthesiology 1995;83:1153–61.[Medline]
  15. Katayama Y, Hatanaka K, Hayashi T, et al. Effects of inhaled nitric oxide in single lung transplantation in rats with monocrotaline-induced pulmonary hypertension. J Heart Lung Transplant 1995;14:486–92.[Medline]
  16. Haniuda M, Dresler CM, Mizuta T, Cooper JD, Patterson GA. Free radical-mediated vascular injury in lungs preserved at moderate hypothermia. Ann Thorac Surg 1995;60:1376–81.[Abstract/Free Full Text]
  17. Elliott SJ, Koliwad SK. Oxidant stress and endothelial membrane transport. Free Radic Biol Med 1995;19:649–58.[Medline]
  18. Juckett MB, Weber M, Balla J, Jacob HS, Vercellotti GM. Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury. Free Radic Biol Med 1996;20:63–73.[Medline]
  19. Pinsky DJ, Naka Y, Chowdhury NC, et al. The nitric oxide/cyclic GMP pathway in organ transplantation: critical role in successful lung preservation. Proc Natl Acad Sci U S A 1994;91:12086–90.[Abstract/Free Full Text]
  20. Adatia I, Lillehei C, Arnold JH, et al. Inhaled nitric oxide in the treatment of postoperative graft dysfunction after lung transplantation. Ann Thorac Surg 1994;57:1311–8.[Abstract]
  21. Okabayashi K, Triantafillou AN, Yamashita M, Aoe M, Cooper JD, Patterson GA. Inhaled nitric oxide reduces lung allograft reperfusion injury. Surg Forum 1994;45:276–8.
  22. Nieding V, Wagner HM. Vergleich der Wirkung von Stickstoffdioxid und Stickstoffmonoxid auf die Lungenfunktion des Menschen. Staub-Reinhalt Luft 1975;35:175–8.
  23. Nishimura M, Hess D, Kacmarek RM, Ritz R, Hurford WE. Nitrogen dioxide production during mechanical ventilation with nitric oxide in adults. Effects of ventilator internal volume, air versus nitrogen dilution, minute ventilation, and inspired oxygen fraction. Anesthesiology 1995;82:1246–54.[Medline]
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