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Ann Thorac Surg 2000;69:210-215
© 2000 The Society of Thoracic Surgeons

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Original Articles

Exhaled nitric oxide correlates with experimental lung transplant rejection

^a Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA

Address reprint requests to Dr Patterson, Division of Cardiothoracic Surgery, Washington University School of Medicine, One Barnes-Jewish Hospital Plaza, Suite 3108 Queeny Tower, St. Louis, MO 63110

Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Increased nitric oxide production accompanies acute lung allograft rejection. Transforming growth factor-ß1 is an immunosuppressive cytokine capable of ameliorating acute rejection. The purpose of this study was to determine whether exhaled nitric oxide (eNO) concentrations correlated with the degree of acute rejection.

Methods. A model of acute lung transplant rejection in the rat was developed, and concentrations of eNO were measured at the time of animal sacrifice. In group 1 (partial immunosuppression), donor lungs were pretreated with transforming growth factor-ß1 before implantation. In group 2 (fulminant acute rejection), no immunosuppression was used. In group 3 (full immunosuppression), recipients received cyclosporine. Group 4 were normal rats.

Results. When measured from both lungs, eNO concentrations were 4.97 ± 0.68 versus 6.73 ± 2.90 ppb for groups 1 and 2, respectively (p = 0.58). When measured selectively from transplanted left lungs, eNO concentrations were 8.61 ± 0.97 versus 42.14 ± 7.27 ppb, respectively (p < 0.001). In groups 3 and 4, eNO concentrations were 1.02 ± 0.21 and 1.51 ± 0.74 ppb, respectively.

Conclusions. Exhaled nitric oxide is elevated in fulminant acute rejection, is reduced after partial immunosuppression using transforming growth factor-ß1 gene therapy, and is in the normal range in cyclosporine-treated animals. The measurement of eNO correlates with the degree of acute lung allograft rejection and may serve as a noninvasive measure of acute lung transplant rejection in the clinical setting.

	Introduction

Top Abstract Introduction Material and methods Results Comment References

 
In lung transplantation, the frequency and severity of acute rejection is the single most important predictor for the development of bronchiolitis obliterans [1]. Almost all lung transplant candidates will experience at least one episode of acute rejection in the postoperative period. The majority of such episodes occur during the first year, although acute rejection has been diagnosed as early as a few days to as late as several years after transplantation [2].

The diagnosis of acute lung transplant rejection is difficult to make without histologic confirmation. The clinical diagnosis is based on a combination of signs and symptoms that mimic an upper respiratory tract infection or bronchitis, and a high index of suspicion is needed. The gold standard for the diagnosis of acute rejection is transbronchial lung biopsy with histologic confirmation of acute rejection [3]. The specificity of transbronchial biopsy for acute rejection has ranged from 90% to 100% with a sensitivity between 61% and 94% [4].

Given the invasive nature of transbronchial lung biopsy, alternative methods of confirming acute rejection have been sought. One novel experimental method that has recently been investigated is the measurement of nitric oxide concentrations in exhaled gas specimens from transplanted lungs. Experimental work has suggested that acute lung allograft rejection is associated with increased enzyme activity of inducible nitric oxide synthase [5]. The measurement of exhaled nitric oxide (eNO) concentrations in the setting of experimental rat lung acute rejection was recently described by Mizuta and coworkers [6]. Increased concentrations of eNO were observed in untreated rat lung allografts, up to 75 times those obtained from contralateral normal lungs. We have also previously reported on the measurement of eNO concentrations in the setting of experimental rat lung allograft rejection [7]. In that report, increased concentrations of eNO were present during acute rejection, with normalization of those concentrations after either immunosuppression or ischemia–reperfusion injury. That work provided the impetus for the current experiments, which focus on the measurement of eNO concentrations during various states of immunosuppression.

In this report, we describe our recent experience with the measurement of eNO in the setting of gene therapy with transforming growth factor-ß1 (TGF-ß1). Because gene therapy with TGF-ß1 results in partial, but not complete, immunosuppression [8], we hypothesized that this would result in decreased, but not normal, concentrations of eNO. Concentrations of eNO were also measured in the setting of complete immunosuppression using cyclosporine and in the absence of systemic immunosuppression.

	Material and methods

Top Abstract Introduction Material and methods Results Comment References

 
Animals
Inbred male Brown Norway rats were used as donors, and inbred male Fischer/F344 rats as recipients (Charles River Laboratories, Wilmington, MA). All animals weighed approximately 270 to 300 g. All animal protocols were approved by the Animal Studies Committee at Washington University. Animals received humane care in compliance with "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Experimental groups
There were four experimental groups. In group 1 (partial immunosuppression), donor lungs were transfected with TGF-ß1 before implantation. In group 2 (fulminant acute rejection), no immunosuppression was used. In group 3 (full immunosuppression), recipients received cyclosporine while group 4 consisted of normal rats.

The left lung transplant technique was used for groups 1, 2 and 3. In group 1, lungs were transfected with the gene encoding for murine TGF-ß1 after lung harvest but before implantation, using an ex vivo technique as previously described [8]. Four preservation solutions were used to ensure that the flush solutions were not a confounding factor in the eNO measurements: low potassium dextran 1% glucose (LPDG, group 1a, n = 4), University of Wisconsin solution (UW, group 1b, n = 4), Wallwork solution (group 1c, n = 5), or modified Eurocollins solution (EC, group 1d, n = 5). Groups 2 and 3 donor lungs were flushed with LPDG. In group 2, animals received no immunosuppression, resulting in acute fulminant graft rejection by postoperative day (POD) 6 or 7 (n = 5). In group 3, animals received intramuscular injections of cyclosporine on POD 2 and 3 (n = 5). Group 4 animals were normal Fischer/F344 nontransplanted controls (n = 4).

Rat left lung transplantation
The rat left transplant technique was used in groups 1, 2, and 3 as described extensively elsewhere [8, 9]. The heart-lung block was initially flushed antegrade with the corresponding preservation solution (LPDG, EC, UW, or Wallwork). In group 1, TGF-ß1 DNA-liposome complexes were prepared as described elsewhere [8], then administered retrograde, to selectively transfect the left lung. A volume of 0.5 mL of construct was mixed with 4.5 mL of preservation solution and administered. This corresponded to 600 µg of TGF-ß1 plasmid DNA. In groups 2 and 3, no retrograde administration of plasmid DNA-liposome complexes was performed. All left lung grafts were stored on ice at 4° to 6°C followed by immediate implantation into Fischer/F344 recipients. Total graft cold ischemia time was 1 to 2 hours.

Cyclosporine administration
Cyclosporin A (25 mg/kg) was administered intramuscularly on POD 2 and POD 3 to animals in group 3. The first 2 animals in this group had a short graft preservation time, approximately 1.5 to 2 hours. The last 3 animals had a prolonged preservation time, approximately 18 hours. Because we have previously shown that a prolonged ischemia–reperfusion injury had no effect on eNO concentrations [7], these data were pooled together to achieve statistical significance in intergroup comparisons. Our previous experience with this particular strain combination showed long-term graft tolerance without detectable rejection at 3 months postoperatively when cyclosporine was administered in this fashion [10].

Measurement of exhaled nitric oxide concentrations
A Sievers Model 280B Nitric Oxide Analyzer was used in all experiments (Sievers Instruments, Boulder, CO), calibrated according to manufacturer specifications. Data were sampled at a rate of 32 samples per second, and stored at 1 sample per second. Before sampling from animals, a background concentration of nitric oxide in inspired gas was obtained by sampling from the ventilator into a closed Mylar balloon. Also, eNO concentrations from normal healthy animals were measured on a daily basis before taking measurements from the experimental groups. Animals were sedated with halothane, intubated with a 14-gauge catheter, and then a sample of exhaled gas was collected and analyzed. This set of animals corresponded to group 4. Data were analyzed using Microsoft Excel 97 (Microsoft Corp, Redwood, WA) to obtain mean values, after discarding the two tail ends of sampled data. A sample data acquisition is shown in Figure 1.

View larger version (17K): [in this window] [in a new window]   Fig 1. A sample data acquisition for approximately 1 minute is shown. The data were then analyzed in a spreadsheet to determine mean values for each acquisition.

After obtaining a measurement of eNO from both lungs, a median sternotomy was performed and the right hilum was dissected. The right pulmonary artery and mainstem bronchus were then clamped to direct ventilation and perfusion to the transplanted left lung allograft. Ventilator settings were adjusted to a tidal volume of 1.5 mL; respiratory rate, 100 breaths/min; positive end-expiratory pressure, 0 cm H₂O; and fraction of inspired oxygen, 100%. Another sample of exhaled gas was collected for 10 minutes, and eNO concentrations were measured.

Statistical analysis
Data were expressed as mean ± standard error of the mean. The standard error of the mean was used instead of standard deviation because each reported eNO value represented an average of many acquired data points. A probability value of less than 0.05 was considered statistically significant. Data were analyzed by one-way or two-way analysis of variance and Fisher’s post hoc multiple comparison test as indicated, using Systat 7 (Systat, Evanston, IL).

	Results

Top Abstract Introduction Material and methods Results Comment References

 
Transforming growth factor-ß1 transfection (group 1) resulted in eNO concentrations that were predictably similar despite using four different preservation solutions. This is shown graphically in Figure 2. Exhaled nitric oxide concentrations obtained from both lungs before median sternotomy were as follows: LPDG (group 1a), 4.92 ± 0.38 ppb; UW (group 1b), 4.04 ± 1.53; Wallwork (group 1c), 5.65 ± 2.07; and EC (group 1d), 5.07 ± 0.97. As predicted, there were no statistical differences between these subgroups: p = 0.724 (1a versus 1b); p = 0.757 (1a versus 1c); p = 0.951 (1a versus 1d); p = 0.497 (1b versus 1c); p = 0.665 (1b versus 1d); and p = 0.793 (1c versus 1d).

View larger version (12K): [in this window] [in a new window]   Fig 2. Average exhaled nitric oxide concentrations in groups Ia (low potassium dextran 1% glucose solution), Ib (University of Wisconsin solution), Ic (Wallwork solution), and Id (modified Eurocollins solution). Notice the similarity in exhaled nitric oxide concentrations between the various preservation solutions. Data from all four preservation solutions were pooled together and shown on the far right of the graph as group I. Error bars represent the standard error of the mean.

When comparing eNO concentrations obtained from both lungs with those obtained selectively from the left lung, only the Wallwork group (1c) showed a statistically significant difference (p = 0.010). The LPDG group (1a) and UW group (1b) showed a trend toward achieving statistical significance (p = 0.174 and p = 0.176, respectively). No significant differences were observed between obtaining the eNO concentration from both lungs compared with the left lung in the modified EC group (p = 0.509).

When data from all four preservation solutions were pooled together, the overall eNO concentration measured from both lungs was 4.97 ± 0.68 ppb. Likewise, the average pooled eNO concentration measured selectively from the transplanted left lung allograft was 8.61 ± 0.97 ppb. There was a statistically significant difference between these two values (p = 0.004). Sufficient statistical power was not present in the earlier subgroups (1a, 1b, and 1d) to detect a statistical difference between eNO concentrations from both lungs compared with the rejecting lung, with sample sizes of 4, 4, and 5, respectively.

The presence of fulminant acute rejection (group 2) resulted in marked increases in the concentrations of eNO from lung allografts. When sampled from both lungs (n = 5), the concentration of eNO was 6.73 ± 2.90 ppb. When sampled selectively from rejecting lung allografts, the concentration of eNO increased to 42.14 ± 7.27 ppb (Fig 3). There was a statistically significant increase in the concentrations of eNO measured selectively from the left lung between group 2 and the pooled result from group 1: 42.14 ± 7.27 versus 8.61 ± 0.97 ppb (p < 0.001). This statistical difference was preserved when comparing the eNO concentration obtained selectively from the left lung in group 2 with any of the subgroups in group 1: p < 0.001 for 1a (LPDG) versus 2, 1b (UW) versus 2, 1c (Wallwork) versus 2, and 1d (EC) versus 2.

View larger version (12K): [in this window] [in a new window]   Fig 3. Average exhaled nitric oxide concentrations in groups I (partial immunosuppression as a result of gene transfection with transforming growth factor-ß1), II (fulminant acute rejection in the absence of systemic immunosuppression), III (full immunosuppression with cyclosporine), and IV (normal, nontransplanted animals). Notice the marked elevation in exhaled nitric oxide concentrations in the setting of fulminant acute rejection (group II). These concentrations decrease, but do not normalize, after partial immunosuppression with transforming growth factor-ß1.

The administration of cyclosporine in group 3 resulted in marked immunosuppression in our model, as previously described [11]. Exhaled nitric oxide concentrations were obtained from both lungs in groups 3 and 4. Selective left lung eNO concentrations were not recorded because of technical reasons at the time. The corresponding concentration of eNO was 1.02 ± 0.21 ppb for group 3 (Fig 3). There was a significant difference between pooled group 1 concentrations obtained from the left lung selectively compared with group 3 (p = 0.013). However, statistical significance could not be achieved when subgroups 1a, 1b, and 1d were compared with group 3 controls, again because of the lack of statistical power with small sample sizes: 3 versus 1a (LPDG), p = 0.13; 3 versus 1b (UW), p = 0.18; and 3 versus 1d (EC), p = 0.22. Only lungs flushed and transfected using Wallwork solution exhibited significant differences in eNO concentrations (p = 0.02).

Group 4, corresponding to normal control animals, had eNO concentrations (obtained from both lungs) similar to those obtained from group 3: 1.51 ± 0.74 ppb, n = 4 (Fig 3). There was a statistically significant difference in eNO concentrations obtained from the left lung in pooled group 1 animals compared with group 4 controls (p = 0.032). However, again because of the small sample size in group 1 subgroups, statistical significance between each subgroup and group 4 controls was present only for subgroup 1c, using the Wallwork solution (p = 0.04). No statistical significance was present when comparing group 4 controls with subgroups 1a, 1b, and 1d: 4 versus 1a (LPDG), p = 0.18; 4 versus 1b (UW), p = 0.24; and 4 versus 1d (EC), p = 0.30.

	Comment

Top Abstract Introduction Material and methods Results Comment References

 
This study demonstrated that eNO concentrations were increased in the presence of acute fulminant lung transplant rejection, were decreased in the presence of partial immunosuppression using TGF-ß1 gene therapy, and were normalized after cyclosporine immunosuppression compared with nontransplanted controls. This study also showed that, in the setting of either partial or fulminant acute rejection with unilateral lung transplantation, eNO concentrations obtained selectively from rejecting lung allografts were higher than those obtained simultaneously from both lungs.

Transforming growth factor-ß1 is a potent immunosuppressive cytokine that has important cellular homeostatic actions, including immunosuppression, tissue repair, inflammation, development, and growth [12]. Some of its immunosuppressive actions include the inhibition of thymocyte and T- and B-cell proliferation, natural killer cell activity, monocyte function, helper T-cell type 2 cellular apoptosis, cytokine and antibody production, and cellular switching [13]. These pleiotropic effects of TGF-ß1 have made it a candidate gene for gene therapy studies, especially in the setting of organ transplantation. The infusion of a recombinant TGF-ß1 protein resulted in improvements in graft survival in the mouse heart [14] and rat heart [15]. In a rat cardiac transplant model, the injection of plasmid TGF-ß1 complexes into the myocardium resulted in the prolongation of graft survival from 12.6 to 26.3 days [16]. More recently, the intracoronary administration of adenoviral vectors carrying the TGF-ß1 gene construct resulted in the prolongation of cardiac allograft survival and in a decrease in acute rejection scores [17].

These encouraging results in experimental heart transplant animal models led us to administer liposomal vectors carrying the TGF-ß1 gene to rat lung allografts to study its effects on acute lung transplant rejection [8]. Transfected allografts had marked improvements in arterial oxygenation compared with controls, with a PaO₂ of 474.2 ± 168.5 versus 102.8 ± 85.3 mm Hg, respectively. Statistically significant reductions in the pathologic grading of acute allograft rejection were noted, for both perivascular and peribronchiolar inflammation [8].

Increased concentrations of eNO have been recently reported in the setting of acute allograft rejection after lung transplantation. In a study of rat right lung allograft rejection with Brown Norway donors and Lewis recipients, eNO concentrations were increased in rejecting animals compared with immunosuppressed animals [6]. The concentration of eNO as measured from both lungs on POD 5 in these untreated lung allografts undergoing acute rejection was 63.9 ± 39.2 ppb compared with 9.1 ± 1.6 ppb in cyclosporine-treated allografts and 6.9 ± 0.5 ppb in isografts [6]. No increases in eNO concentrations were detected in the setting of ischemia–reperfusion injury [7]. The concentration of eNO seemed to depend on the particular strain combination used to produce acute allograft rejection. Using Brown Norway donors and Lewis recipients in the absence of immunosuppression, the concentration of eNO as measured from the rejecting left lung was even higher, at 57.1 ppb [18].

This report integrates these two experimental techniques, namely the measurement of eNO concentrations and gene transfection with TGF-ß1, in the setting of acute allograft rejection in the rat. As predicted, concentrations in the presence of partial immunosuppression with TGF-ß1 were lower than those in the setting of fulminant untreated acute rejection. After immunosuppression with cyclosporine, eNO concentrations were not significantly different from control nontransplanted animals. This reflects the higher potency of cyclosporine in treating rat allograft rejection compared with TGF-ß1 gene transfection.

Exhaled nitric oxide concentrations measured from rejecting left lung allografts were higher than those measured from both lungs simultaneously. This is likely because of several reasons. First, when sampled from both lungs, the concentration of eNO reflects dilutions from the normal nontransplanted native right lung, which presumably should have normal concentrations of eNO compared with the rejecting lung allograft. Second, after clamping the right hilum, increased recruitment of left lung alveoli takes place as atelectatic areas are ventilated, thereby increasing the concentration of eNO in this setting. Third, the presence of acute rejection results in decreased lung compliance, resulting in an even lower left lung contribution to overall exhaled gas when both lungs are ventilated compared with single-lung ventilation.

Three recent reports have investigated the feasibility of measuring eNO concentrations after human lung transplantation. In a study of 108 lung transplant recipients, the presence of acute rejection correlated with elevations in eNO concentrations: 51.1 ± 6.3 ppb versus 19.5 ± 1.1 ppb for acute lung allograft rejection versus stable lung transplant recipients, respectively. The cohort of patients with histologically documented acute rejection, however, was small, representing only 8 patients [19]. In another study of 7 patients with bronchiolitis obliterans syndrome, increased concentrations of eNO were found, which were statistically different from lung transplant recipients without evidence of chronic lung rejection: 19.6 ± 7.5 ppb versus 10.8 ± 1.9 ppb, respectively [20]. A more recent study of 104 lung transplant recipients and 55 healthy controls revealed elevated concentrations of eNO in the presence of lymphocytic bronchiolitis, early bronchiolitis obliterans, and infection: 10.3 ± 1.4 ppb versus 10.0 ± 1.3 ppb and 10.5 ± 1.0 ppb, respectively, compared with clinically well recipients, whose concentrations of eNO were 5.3 ± 0.5 ppb [21]. The reasons for the discrepancy in these three studies in eNO concentrations in the presence of infection and bronchiolitis obliterans syndrome are not clear.

In summary, in the setting of rat left lung allograft rejection, eNO concentrations were measured in three settings: fulminant acute rejection without immunosuppression, partially treated rejection using gene therapy with TGF-ß1, and immunosuppression with cyclosporine. Concentrations were significantly elevated in acute rejection, decreased after gene transfection with TGF-ß1, and normalized after immunosuppression. It appears that the measurement of eNO concentrations after lung transplantation correlates with the degree of acute allograft rejection. This may be useful in the clinical setting to differentiate between various clinical scenarios after lung transplantation.

	Acknowledgments

 
The authors thank Richard B. Schuessler, PhD, for assistance in the statistical analyses. This work was supported by National Institutes of Health grants 1 R01 HL-41281 (to G. Alexander Patterson) and 1 F32 HL-09751-01 (to Bassem N. Mora). Carlos H. R. Boasquevisque was supported by the Federal University of Rio de Janeiro-University Hospital Clementino Fraga Filho, Brazil.

	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): Bassem N. Mora Carlos H.R. Boasquevisque G. Alexander Patterson Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mora, B. N. Articles by Patterson, G. A. Search for Related Content PubMed PubMed Citation Articles by Mora, B. N. Articles by Patterson, G. A.