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J Thorac Cardiovasc Surg 1994;108:913-921
© 1994 Mosby, Inc.

CARDIAC AND PULMONARY REPLACEMENT

Inhibition of reperfusion injury by human thioredoxin (adult T-cell leukemia-derived factor) in canine lung transplantation

Kazuyuki Yagi, MD, Chunjiang Liu, MD, Toru Bando, MD, Hiroyasu Yokomise, MD, Kenji Inui, MD, Shigeki Hitomi, MD, Hiromi Wada, MD


Kyoto, Japan

From the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University, Kyoto, Japan.

Received for publication Feb. 9, 1994. Accepted for publication May 10, 1994. Address for reprints: Hiromi Wada, MD, Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University, Shogoin Sakyo-ku, Kyoto 606, Japan.

Abstract

Human thioredoxin, which was previously recognized as adult T-cell leukemia-derived factor, has many physiologic activities, one of which is a radical scavenger effect. Its ability to reduce reperfusion injury was assessed in vivo in a canine lung transplantation model. In 19 dogs, left lung allotransplantation was performed after 100 minutes of warm ischemia. The function of the transplanted lung was assessed after clamping of the contralateral pulmonary artery. In the human thioredoxin group (n = 6), human thioredoxin 30 mg/kg was given to the recipients during reperfusion. In the N-acetylcysteine group (n = 5), N-acetylcysteine 150 mg/kg, known as a radical scavenger, was given in the same manner. In both groups, arterial oxygen tension was significantly higher than in the control group (n = 8). In the human thioredoxin group, peak inspiratory pressure was significantly lower than in the control group. Macroscopic and microscopic examinations showed an almost normal appearance of the lung tissues in the human thioredoxin and N-acetylcysteine groups, in contrast to the abnormal findings in the control group. Thus it would appear that human thioredoxin has a protective effect on transplanted lungs, as does N-acetylcysteine, and that its action may be a radical scavenger effect. (J THORACCARDIOVASCSURG1994;108:913-21)

The development of pulmonary edema early in the postoperative period after lung transplantation is called pulmonary reimplantation response.Go 1 Although this response is believed to be due in part to the transection of pulmonary arteries and veins, nerves, lymphatic vessels, and bronchial arteries, the major factor is thought to be ischemia-reperfusion injury.Go 2 Ischemia of the organs cannot be avoided in organ transplantation. Meanwhile, the restricting factor in clinical lung transplantation on a global scale is the shortage of donor organs. Hence it is important that the viability of the organs for transplantation be well maintained. Active oxygen species are known to be among the causes of ischemia-reperfusion injury. Experiments with various types of free radical scavengers have been performed, and their usefulness has been reported.Go Go 3-8

Human thioredoxin/adult T-cell leukemia-derived factor (hTX/ADF) is a polypeptide with a molecular weight of approximately 12,000, and in the center of its activity is a Cys-Gly-Pro-Cys amino acid sequence. The reversible reaction of the two Cys residues from dithiol to disulfide causes it to be deeply involved in the oxidation-reduction reactions in the body. The radical scavenger effect of hTX/ADF, used to eliminate hydrogen peroxide produced by the xanthine oxidases, has been reported by Mitsui, Hirakawa, and Yodoi.Go 9 Moreover, in our study of an in vivo rat lung reperfusion injury model, we found that hTX/ADF inhibits the formation of pulmonary edema and improves the partial pressure of oxygen.Go 10 In the present in vivo study, we tested the inhibition of reperfusion injury by hTX/ADF in a canine lung transplantation model.

MATERIAL AND METHODS

Donor harvest
Nineteen adult mongrel dogs weighing approximately 10 kg were anesthetized with thiopental (100 to 150 mg). Nitrous oxide was used with 1.0% halothane for anesthesia during the operations. Pancuronium was administered for muscle relaxation. The respirator was set to the following: inspired oxygen fraction = 0.5, tidal volume = 20 ml/kg, positive end-expiratory pressure = 5 cm H2O, and respiratory rate = 15 beats/min (model SN-480-3, Shinano Industrial Company, Tokyo, Japan). A thermodilution catheter was inserted into the femoral vein, and pulmonary artery pressure, pulmonary artery wedge pressure, and cardiac output were measured. Peak inspiratory pressure was measured and blood gas analysis was done. A midline sternotomy incision was made and a cardiopulmonary block was harvested after the intravenous injection of heparin, 200 U/kg. The warm ischemic time was recorded starting immediately after the superior and inferior venae cavae had been ligated. After preparation of the left lung block, the lung was isolated and placed in the left thoracic cavity of the recipient, which had already been prepared for the transplant.

During this period, a thermometer (temperature sensor, Terumo Company, Tokyo, Japan) was placed in the thoracic cavity of the recipient and the intrathoracic temperature was monitored.

Recipient
Using the method described previously, we induced and maintained anesthesia in 19 adult mongrel dogs, the weights of which were the same as those of the donor dogs. The femoral artery was cannulated and a thermodilution catheter was inserted via the femoral vein. Pulmonary artery and peak inspiratory pressures were monitored. After a Nelaton tube (Izumo Company, Tokyo, Japan) had been passed through the right main pulmonary artery, the left lung was resected and transplanted by our previously reported method.Go 11 The left atrium was unclamped as the vessels were anastomosed, and the pulmonary artery and bronchus were unclamped at the time of reperfusion. The warm ischemic time ended as reperfusion was started. The total warm ischemic time was 100 minutes. This length of time, as reported in our previous study,Go 11 is known to cause reversible injury.

Experiment group
Nineteen recipient dogs were divided into three groups: eight dogs in the control group, six in the hTX group, and five in the N-acetylcysteine (NAC) group. In the hTX group, recombinant hTX 30 mg/kg was dissolved in 100 ml phosphate-buffered saline and was drip-infused over a 30-minute period. In the NAC group, NAC 150 mg/kg was dissolved in 100 ml phosphate-buffered saline and drip-infused over a 30-minute period. In the control group, 100 ml phosphate-buffered saline was administered over a 30-minute period.

NAC was provided by Eisai Company, Tokyo, Japan. Recombinant hTX was provided by Ajinomoto Company, Kawasaki, Japan. The complementary deoxyribonucleic acid of hTX was expressed in Escherichia coli and hTX protein accumulated in the bacterial cells was purified by ion-exchange chromatography. The purified protein was fully reduced by the treatment with dithiothreitol. The resulting samples were more than 99% pure, as determined by densitometer analysis after sodium dodecylsulfate–polyacrylamide gel electrophoresis and silver staining. Content of bacterial endotoxin was determined to be less than 4 pg/mg protein by quantitative chromogenic limulus amebocyte lysate method.

Evaluation criteria
At 10, 40, 70, and 130 minutes after transplantation, the right main pulmonary artery was clamped for 5 minutes and arterial blood gases, pulmonary artery pressure, and peak inspiratory pressure were measured. Pulmonary wedge pressure and cardiac output were measured at 130 minutes, and the results were used to calculate the pulmonary vascular resistance. The dogs were then killed. The wet/dry ratios were determined, and the lungs were examined histologically with hematoxylin-eosin staining and immunohistologic staining with an enzyme-antibody method using anti-hTX antibody. All values were expressed as mean ± standard error, and differences were evaluated with analysis of variance. A p value less than 0.05 was considered significant.

All animals received humane care in compliance with the "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 No. 86-23, revised 1985).

RESULTS

All the dogs in the three groups survived until they were killed 130 minutes after transplantation. No significant difference was observed among the three groups in regard to weight, intrathoracic temperature, and time of retention of the donor lung in the thoracic cavity (GoTable I).


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  		Table I. Experimental groups
 
Partial pressure of oxygen in arterial blood
(Fig. 1). The preoperative baseline value in the donors and value 130 minutes after transplantation were 278 ± 8 and 260 ± 33 torr, respectively, in the hTX group. In the NAC group, the values were 273 ± 17 and 247 ± 49 torr, respectively, and in the control group they were 270 ± 6 and 96 ± 10 torr, respectively. Throughout the observation period, the hTX group had significantly higher partial pressure of oxygen in the arterial blood than did the control group (p < 0.05, p < 0.01). No statistically significant difference was observed between the hTX and NAC groups.



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  		Fig. 1. Arterial oxygen tension of transplanted lungs. Arterial oxygen tensions after reperfusion were excellent both in the hTX group and in the NAC group, whereas they decreased after reperfusion. SE, Standard error.

 
Peak inspiratory pressure
(Fig. 2). In the recipients the preoperative baseline value and the value at 130 minutes in the recipient were 14.2 ± 1.4 and 12.5 ± 1.0 cm H2O, respectively, in the hTX group and 14.6 ± 0.4 and 16 ± 2.0 cm H2O, respectively, in the NAC group; in the control group, they were 12.4 ± 0.9 and 17.4 ± 1.1 cm H2O, respectively. The peak inspiratory pressure in the hTX group was lower than in the other two groups. It was significantly lower in the hTX group than in the control group 130 minutes after the operation (p < 0.01).



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  		Fig. 2. Peak inspiratory pressure of transplanted lungs. In the NAC group and the control group, the peak inspiratory pressures increased with the duration of reperfusion, whereas in the hTX group the values remained almost constant after reperfusion. SE, Standard error.

 
Pulmonary vascular resistance
(Fig. 3). The pulmonary vascular resistance of the dogs in the hTX group measured at 130 minutes was 864 ± 256 dyne · sec · cm-5 and 2256 ± 438 dyne · sec · cm-5 in the NAC group. In the control group it was 1830 ± 255 dyne · sec · cm-5. There was no significant difference among the three groups. The pulmonary vascular resistance measured before transplantation without clamping of the right pulmonary artery was 519 ± 108 dyne · sec · cm-5 in the hTX group, 755 ± 142 dyne · sec · cm-5 in the NAC group, and 487 ± 134 dyne · sec · cm-5 in the control group—not a statistically significant difference.



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  		Fig. 3. Pulmonary vascular resistance of transplanted lungs 130 minutes after reperfusion. SEM, Standard error of the mean.

 
Pulmonary artery pressure
(Fig. 4). In the donors the preoperative baseline value and value at 130 minutes in the donor were 19.3 ± 3.4 and 31.5 ± 6.8 mm Hg, respectively, in the hTX group and 22.0 ± 1.4 and 34.8 ± 6.1 mm Hg, respectively, in the NAC group. In the control group, the values were 16.6 ± 2.0 and 30.9 ± 10.8 mm Hg. The differences among the three groups were not statistically significant.



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  		Fig. 4. Pulmonary artery pressure (PAP) of transplanted lungs. SE, Standard error.

 
Wet/dry weight ratios Go(Table I)
The wet/dry weight ratios were 5.7 ± 0.2 in the hTX group, 5.4 ± 0.4 in the NAC group, and 6.3 ± 0.4 in the control group. The differences among the three groups were not statistically significant.

Histologic findings
Macroscopic findings (Fig 5A).
The transplanted lungs in both the hTX and NAC groups were pink and looked normal, but in the control group dogs the lungs were red and edematous.



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  		Fig. 5A. Macroscopic findings of transplanted lungs. Top, hTX; middle, NAC; bottom, control.

 
Hematoxylin-eosin staining (Fig. 5B).
Thickening of the alveolar interstitium was not seen, and normal findings were observed in subjects in the hTX and NAC groups. However, in the control group, thickening of the alveolar interstitium, exudation into the alveolar spaces, and mild cellular infiltration were observed.



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  		Fig. 5B. Microscopic findings of transplanted lungs. In the control group interstitial thickening of the alveolar wall and the exudates into the alveolar space were noted. Top, hTX; middle, NAC; bottom, control. (Hematoxylin-eosin staining; original magnification x100.)

 
Immunohistologic staining (Fig. 5C).
The lung tissues in group hTX were definitely stained darker with immunohistologic staining with anti-hTX polyclonal antibody than in the other two groups. The vascular endothelial cells were also stained, and uptake of hTX by the endothelial cells was observed.



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  		Fig. 5C. Immunohistologic staining of transplanted lungs. The endothelium of pulmonary artery was stained by anti-hTX polyclonal antibody in the hTX group. Top, hTX; middle, NAC; bottom, control. (Original magnification x400.)

 
DISCUSSION

Ischemia-reperfusion injury always occurs after organ transplantation. With the current long-term preservation of organs by organ flushing, ischemia-reperfusion injury is likely to be even more severe. Prevention of ischemia-reperfusion injury is important in lung transplantation. It is widely known that active oxygen species are mainly associated with the occurrence of ischemia-reperfusion injury.Go Go 12-15 In the lung, active oxygen species are produced in the vascular endothelial cells after reperfusion, and they can injure the vascular endothelial cells.Go 15 Taking into consideration that xanthine oxidase activity is abundant in the vascular endothelial cells,Go Go 15,16 it can be speculated that ischemia-reperfusion injury in lung transplantation is caused by the production of active oxygen species from the xanthine oxidases. Injury caused by neutrophils is triggered 30 minutes to a few hours after reperfusion as a result of the damage to the vascular endothelial cells. Consequently, up-regulation of intracellular adhesion molecule occurs and leads to the secondary accumulation of neutrophils, which increases the severity of the injury.Go Go 14,18 As can be seen from our experiment, even though arterial oxygen tension decreased within 130 minutes after reperfusion and functional damage to the lung was seen, there was little infiltration of neutrophils into the lung tissues.

hTX/ADF is a polypeptide with a molecular weight of 12,000 and is composed of 104 amino acids. It was isolated from an adult T-cell leukemia cell culture in 1985 and was originally described as a derivative of interleukin-2 receptor {alpha}-chain.Go 19 Results of later studies on gene cloning revealed that hTX/ADF is actually human thioredoxin.Go Go 20,21 Thioredoxin is an oxidation-reduction protein possessing an SH group found abundantly in Escherichia coli, yeast, plants, and animals.Go 22 Its molecular weight is approximately 12,000, and it possesses a characteristic partial structure: Try-Cys-Gly-Pro-Cys-Lys (WCGPCK). The SH groups in the two Cys amino acids are involved in the oxidation-reduction reaction. Mitsui, Hirakawa, and YodoiGo 9 proved the inhibitory action of hTX/ADF against active oxygen species that are induced by xanthine oxidases. They demonstrated that this action is not affected by superoxide dismutase and proved that hTX/ADF is a scavenger of hydrogen peroxide because active oxygen species were eliminated by catalase.

We prepared a rat model of ischemia-reperfusion injury and confirmed that the group treated with hTX showed a significant increase in arterial oxygen tension and a significantly lower wet/dry weight ratio.Go 10 In this study, we investigated the inhibitory effect of hTX/ADF on a canine lung transplantation model. In our previous study, we reported that the limit of warm ischemic time is 120 minutes before function of the transplanted lung fails.Go 11 We adhered to this principle in this study also. Because it is difficult to determine whether the injury is due to active oxygen species in an in vivo experiment, one group of dogs was given NAC, known for its radical scavenger effect.Go Go 23,26 Although NAC was originally used as a mucus catalyst, it is now used as an antidote against acetaminophen toxicity and in the treatment of hemorrhagic cystitis caused by alkylating agents such as cyclophosphamide. Its pharmacologic efficacy in the treatment of hemorrhagic cystitis is believed to be a radical scavenger effect.Go 27 Its usefulness in the treatment of adult respiratory distress syndrome has also been reported.Go Go 28,29 In this study, NAC, which has the same thiol group as thioredoxin, was administered as a positive control. Both the hTX and NAC groups demonstrated a significant increase in oxygenation. It is speculated that the prevention of damage to the transplanted lung by hTX/ADF and NAC is a result of the antioxidant effect.

Possible adverse reactions were sought, but no changes in cardiovascular kinetics were seen in the dogs given hTX/ADF, perhaps because of the homologous characteristics of thioreodoxin with other forms of life. Changes in cardiovascular kinetics were not observed in the NAC group either.

Immunohistochemistry tests using anti-hTX/ADF antibodies showed no hTX/ADF in the NAC or control groups. Because hTX/ADF was found in the tissues, especially in the vascular endothelial cells, in the dogs treated with hTX/ADF, it was clear that what was seen was the administered hTX/ADF itself and that its uptake by the target tissues was excellent.

CONCLUSION

In allotransplantation of the left lung in a canine model of warm ischemia, recombinant hTX inhibited ischemia-reperfusion injury, and it is believed that it will be useful in lung transplantation. Taking into consideration the fact that ischemia-reperfusion injury is also inhibited by NAC in the experimental model, its action strongly suggests the involvement of a radical scavenger effect.

References

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