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Ann Thorac Surg 1997;63:954-959
© 1997 The Society of Thoracic Surgeons

Original Article: General Thoracic

EPC-K1 Is Effective in Lung Preservation in an Ex Vivo Rabbit Lung Perfusion Model

Itaru Nagahiro, MD, Motoi Aoe, MD, Motohiro Yamashita, MD, Hiroshi Date, MD, Akio Andou, MD, Nobuyoshi Shimizu, MD

Second Department of Surgery, Okayama University School of Medicine, Okayama, Japan

Accepted for publication October 29, 1996.


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background. l-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6yl-hydrogen phosphate] potassium salt (epc-k1) is a phosphate diester of {alpha}-tocopherol and ascorbic acid. It has been reported that EPC-K1 inhibits lipid peroxidation and phospholipase A2. We hypothesized that EPC-K1 might enhance lung preservation and reduce the degree of posttransplantation lung dysfunction.

Methods. Eighteen rabbits were divided into three groups, as follows: group 1, no preservation (n = 6); groups 2 (n = 6) and 3 (n = 6), 24 hours of preservation at 8°C. Low-potassium dextran–1% glucose solution was used for flushing and immersion in all groups, but EPC-K1 (0.5 mg/L) was added to the solution used in group 3. After storage the left lung was reperfused with autologous blood and ventilated using a membrane oxygenator in an isolated rabbit lung reperfusion model. The grafts used in the group 1 rabbits were perfused for 5 hours to confirm the reliability of this model, and the grafts used in the group 2 and 3 rabbits were perfused for 2 hours. Pulmonary arterial pressure, airway pressure, blood gas analysis, and the lipid peroxide level of the perfusate were assessed. The lipid peroxide levels of the lung tissue before and after storage and the wet–dry weight ratio of the perfused lung were determined in groups 2 and 3.

Results. Superior graft function was noted in group 3 in terms of all indices. The lipid peroxide level in the perfusate and the wet–dry weight ratio were also suppressed in group 3. The lipid peroxide level in the lung tissue did not change during storage in either group.

Conclusions. The administration of EPC-K1 in the flush and preservation solution helps enhance lung graft function and suppresses lipid peroxidation after reperfusion.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
See also page 959.

Improved lung preservation after longer periods of ischemia will cause the donor pool to be increased because it will allow the retrieval of organs from greater distances [1]. Efforts to accomplish this objective have mostly focused on the addition of drugs or other substances to a single-flush lung perfusion regimen. Some of the main agents that have been studied have been free radical scavengers, such as dimethylthiourea [2], allopurinol [3, 4], and superoxide dismutase [4]. The newly developed compound, L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6yl-hydrogen phosphate] potassium salt (epc-k1), has been reported to be a potent hydroxy radical scavenger [5] and an inhibitor of phospholipase a2 [6]. these properties ameliorate reperfusion injury [7–10] and inflammation [11]. however, the effect of epc-k1 on organ preservation needs to be studied.

Although rabbits [12, 13] and rats have been used in many isolated lung perfusion models [14], the duration of the experiments has been short and therefore the value of the findings may be limited [1]. In this study we installed a membrane oxygenator in the closed circuit of an isolated rabbit lung reperfusion model to serve as a deoxygenator in order to lengthen the duration of the experiments and examined the effect of EPC-K1 on lung preservation.


   Material and Methods
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Donor Procedure
Male New Zealand white rabbits weighing 2.5 to 3.5 kg were premedicated with subcutaneously administered atropine sulfate (0.2 mg/kg) and ketamine (50 mg/kg) and anesthetized with intravenously administered sodium thiopental (20 mg/kg). Heparin (600 U/kg) was administered into the ear vein. Each animal was intubated with a endotracheal tube (4 mm in diameter) through a cervical tracheostomy, the tubing was connected to a volume-cycled respirator (model OP-210; Okazaki Sangyo Co Ltd, Tokyo, Japan), and the lungs were ventilated with a fraction of inspired oxygen of 1.0, a tidal volume of 10 mL/kg, a respiratory rate of 25 breaths/min, and a positive end-expiratory pressure of 0.5 cm H2O. After median sternotomy, thymectomy, and pericardiotomy were performed, the ascending aorta and main pulmonary artery were isolated. A catheter (3 mm in diameter) was introduced into the main pulmonary artery through the right ventricular outflow tract, and the pulmonary arterial pressure and airway pressure were monitored (Polygraph 363; NEC-Sanei Co Ltd, Okayama, Japan) and recorded (Omniace RT 2108A; NEC-Sanei Co Ltd) by means of a side port.

The main pulmonary artery was ligated around the cannula, and approximately 80 mL of blood was drawn by right ventricular puncture (the blood obtained was heparinized with an additional 2,000 units of heparin sodium, mixed with 14 mL of citrate-phosphate-dextrose solution, and stored at 8°C for reperfusion). The aorta was ligated and divided, and the left ventricle was transected. The lung was flushed by gravity from a height of 45 cm with 200 mL of cold (8°C) low-potassium dextran–1% glucose solution [15]. The trachea was clamped after the lungs were hyperinflated once by occlusion of expiratory flow to eliminate atelectasis. The right hilum was then ligated with umbilical tape, and the heart-lung blocks were stored in the solution at 8°C until reperfusion.

Reperfusion
A fenestrated drainage catheter (10 mm in diameter) was inserted into the left ventricle through the apex, and the other end was connected to a reservoir set 10 cm below the left ventricle. A membrane oxygenator (Melapolypropylene, type 30EC; Senko-Ikakogyo Co Ltd, Tokyo, Japan) was primed with approximately 80 mL of heparinized saline solution and installed between the reservoir and the heart-lung block. The stored blood was warmed to 37°C and used to fill the reservoir and the tubes.

The heart-lung block was placed in a warm (37°C), humidified chamber, and the reservoir was placed in a 37°C water bath. The left lung alone was ventilated (room air, tidal volume of 5 mL/kg, positive end-expiratory pressure of 0.5 cm H2O, respiratory rate of 25 breaths/min) and reperfused for 2 minutes at a rate of 20 mL/min with a roller pump (Blood Pump NIP BP-1; Nipuro Co Ltd, Osaka, Japan). The flow rate was increased in increments of 10 mL/min to a total flow rate of 70 mL/min at 7 minutes (assessment time point of 0 minute). After a sample of blood was obtained from the outflow cannula for the purpose of determining baseline data, the lung was inflated with 100% oxygen and the membrane oxygenator was infused with mixed gas (10% carbon dioxide, 90% nitrogen) to deoxygenate the blood from the lung. The infusion rate of the mixed gas was controlled to maintain a partial oxygen (PIO2) and carbon dioxide (PICO2) tension of inflow blood of around 50 and 70 mm Hg, respectively.

Experimental Groups
Eighteen male New Zealand white rabbits (weight, 2.5 to 3.5 kg) were divided into three groups. The lungs from the group 1 rabbits (n = 6) were flushed and stored during the preparation of the circuit, then reperfused immediately. The lungs from the group 2 (n = 6) and group 3 (n = 6) rabbits were flushed and stored for 24 hours, but EPC-K1 (Senju Pharmaceutical Co, Osaka, Japan) was added to the low-potassium dextran–1% glucose solution (0.5 mg/L) used for the flushing and immersion of the lungs from the group 3 rabbits. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" (NIH publication 85-23, revised 1985).

Assessment of the Graft
To confirm the reliability of this model, the lungs of group 1 rabbits were reperfused for 300 minutes. The partial oxygen and carbon dioxide tension of outflow blood, PIO2, PICO2, mean pulmonary arterial pressure, peak airway pressure, and serum lipid peroxide (LPO) level of outflow blood were measured at 0, 10, 30, and 60 minutes and every 60 minutes thereafter to 300 minutes.

The same measurements were performed in group 2 and 3 lungs at 0, 5, 10, and 20, minutes and every 20 minutes thereafter to 120 minutes. Tissue samples of the right lobe of the lung were obtained before and after preservation to determine the change in the tissue LPO level during preservation. The wet–dry weight ratio of the left lung was measured after reperfusion for 120 minutes.

Lipid Peroxide Analysis
Blood samples were centrifuged at 3,000 g for 10 minutes at 4°C and stored at -60°C. Tissue samples were then rapidly frozen by immersion in liquid nitrogen and stored at -60°C. The tissue samples (200 to 300 mg wet weight) were homogenized and diluted tenfold with ice-cold 1.15% potassium chloride, and 0.1 mL of the homogenate was analyzed. Analysis of the serum and tissue LPO levels was done using a methylene blue derivative method [16]. Briefly, in this method, hemoglobin catalyzes the reaction of hydroperoxides with methylene blue derivative and an equimolar methylene blue is formed. Thus the LPO level is determined by measuring the intensity of color development caused by the formation of methylene blue. The reagents (Determiner LPO) were purchased from Kyowa Medex Co Ltd, Tokyo, Japan.

Statistical Analysis
All values are expressed as the mean ± standard error of the mean. Statistical analysis was performed with one-way analysis of variance with repeated measures. A p value of less than 0.05 was considered significant.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Lung Function and Serum Lipid Peroxide Level
The body weights (groups 1, 2, and 3: 3.0 ± 0.1, 2.9 ± 0.1, and 3.0 ± 0.1 kg, respectively), mean flushing times (groups 1, 2, and 3: 85 ± 3, 89 ± 5, and 86 ± 4 seconds, respectively), mean flushing pressures (groups 1, 2, and 3: 10.8 ± 0.5, 13.2 ± 1.2, and 11.2 ± 0.9 mm Hg, respectively), and the hematocrits of the perfusate (groups 1, 2, and 3: 20.2% ± 1.3%, 19.7% ± 0.6%, and 21.5% ± 0.8%, respectively) were similar in all groups. The total ischemic times (groups 1, 2, and 3: 0.5 ± 0.1, 24.2 ± 0.8, 24.0 ± 0.3 hours, respectively) were also similar for groups 2 and 3.

The PIO2 in group 1 remained close to 50 mm Hg throughout the experiment (at 10 minutes, 54.1 ± 2.1 mm Hg; at 300 minutes, 45.9 ± 5.0 mm Hg), and there were no significant differences in the values between any time points, whereas the partial oxygen tension of outflow blood showed good oxygenation until the 180-minute assessment (345.1 ± 58.5 mm Hg). The value then declined to 229.0 ± 75.9 mm Hg at 240 minutes because of lung edema. The outflow value was significantly higher than the inflow value throughout reperfusion for 300 minutes (p < 0.01). The PICO2 was 67.3 ± 3.9 mm Hg after 10 minutes of reperfusion and remained close to 70 mm Hg throughout the entire reperfusion period with no significant change. The peak airway pressure was 6.3 ± 0.6 mm Hg at the beginning of reperfusion and increased to 10.0 ± 1.3 mm Hg at 300 minutes, representing a significant increase (p < 0.05). The pulmonary arterial pressure was 15.2 ± 0.5 mm Hg at the beginning of reperfusion and rapidly decreased to 9.7 ± 0.6 mm Hg at 30 minutes, representing a significant decrease (p < 0.05), then it gradually increased again and was found to be 14.6 ± 0.7 mm Hg at the 300-minute assessment, representing a significant increase (p < 0.05). The serum LPO level was 0.5 ± 0.1 nmol/mL at 10 minutes, and it was significantly increased after 180 minutes of reperfusion (at 180 minutes, 1.4 ± 0.3 nmol/mL [p < 0.05]; at 300 minutes, 2.1 ± 0.5 nmol/mL [p < 0.01]).

The PIO2 and PICO2 in group 2 and 3 lungs also remained close to 50 and 70 mm Hg, respectively, and no significant differences between the two groups in this regard were found throughout the experiment. The partial oxygen tension of outflow blood remained over 400 mm Hg in group 3 lungs until the 100-minute assessment and was significantly higher than that in group 2 lungs at 120 minutes (groups 1, 2, and 3: 364.5 ± 54.7, 140.0 ± 58.5, and 391.1 ± 60.0 mm Hg, respectively) (Fig 1Go). The partial carbon dioxide tension of outflow blood of group 3 lungs remained lower than that of group 2 lungs, and there were significant differences from the 80-minute assessment (groups 1, 2, and 3 at 120 minutes: 61.4 ± 3.6, 70.2 ± 3.1, and 54.3 ± 1.7 mm Hg, respectively). The peak airway pressure of group 3 lungs remained at or below 10 mm Hg throughout the experiment and was significantly lower than that of group 2 lungs at the 120-minute assessment (groups 1, 2, and 3: 7.7 ± 0.2, 13.8 ± 1.3, and 9.8 ± 1.0 mm Hg, respectively) (Fig 2Go). The pulmonary arterial pressure of group 3 lungs was lower than that of group 2 lungs throughout the experiment and showed significant differences after the 60-minute assessment (groups 1, 2, and 3 at 120 minutes: 14.7 ± 2.5, 25.3 ± 4.0, and 10.0 ± 1.1 mm Hg, respectively) (Fig 3Go).



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  		Fig 1. . Changes in partial oxygen tension (PoO2) and partial carbon dioxide tension (PoCO2) of the outflow blood. Data are shown as the mean ± the standard error of the mean. (* = p < 0.05 compared with group 1; {dagger} = p < 0.05 and {dagger}{dagger} = p < 0.01 compared with group 3.)

 


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  		Fig 2. . Changes in peak airway pressure (AWP). Data are shown as the mean ± the standard error of the mean. (* and § = p < 0.05 compared with group 1; {dagger} = p < 0.05 compared with group 3.)

 


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  		Fig 3. . Changes in mean pulmonary arterial pressure (PAP). Data are shown as the mean ± the standard error of the mean. (** = p < 0.01 compared with group 1; {dagger} = p < 0.05 and {dagger}{dagger} = p < 0.01 compared with group 3.)

 
The serum LPO level in group 3 lungs also remained at or below 1.0 nmol/mL throughout the reperfusion period and differed significantly from the levels measured in group 2 lungs at 100 minutes (groups 1, 2, and 3 at 120 minutes: 1.2 ± 0.3, 3.4 ± 1.0, and 1.0 ± 0.2 nmol/mL, respectively) (Fig 4Go).



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  		Fig 4. . Changes in serum lipid peroxide (LPO). Data are shown as the mean ± the standard error of the mean. (** = p < 0.01 compared with group 1; {dagger} = p < 0.05 and {dagger}{dagger} = p < 0.01 compared with group 3.)

 
The Wet–Dry Weight Ratio
The wet–dry weight ratios of the left lung of group 3 rabbits were significantly lower than those of group 2 rabbits (p < 0.05) (Table 1Go).


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  		Table 1.. Wet–Dry Weight Ratio and Tissue Lipid Peroxide Levela
 
Tissue Lipid Peroxide Level
The tissue LPO levels in the lungs of group 2 and 3 rabbits did not change significantly before and after storage, and there were no significant differences between the two groups in this regard.


   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
The isolated rabbit lung reperfusion model has been used to evaluate preserved lung function and has yielded valuable information in this regard. Wang and associates [12] developed an open-circuit perfused isolated rabbit lung model. In this model the blood perfusate was discarded, creating the need for as much as 400 mL of blood (using 3 to 4 additional animals), and the reperfusion time was as short as 10 minutes. Weder and colleagues [13] modified the model by perfusing the isolated lung in a closed system with the paracorporeal circulation routed through an anesthetized rabbit. In this model the reperfusion time could be prolonged up to 1 hour, but the method was rather complicated and the use of an animal in the circuit made it more unstable. In addition, the rabbit was not a continuous deoxygenator, so the gas exchange capacity of the lung could not be estimated continuously. In the present study a membrane oxygenator was installed as a deoxygenator in a closed-circuit reperfusion model and stable deoxygenation was confirmed throughout the experiment. The membrane oxygenator helped maintain the PIO2 and PICO2, enabled the gas exchange taking place in the lungs to be estimated continuously throughout the experiment, and fixed the influences from the model other than the lungs. Consequently, the reperfusion time could be prolonged despite the increased perfusion flow rate so that lung function could be evaluated more precisely. In addition, by using blood from the donor rabbit for reperfusion the number of rabbits used could be reduced.

The perfusate hematocrit did not differ for any group because hemodilution reduces early pulmonary ischemia reperfusion injury [17]. A perfusion flow rate of 70 mL/min (approximately half that of a live rabbit) was chosen because at higher flow rates edema developed so quickly in the grafts that there were no differences between control and study groups. Although this remains a limitation to this model, it is minimized by focusing the evaluation on graft function.

Findings from recent studies have indicated that oxygen-derived free radicals generated during reperfusion after the ischemic episode can damage allografts [18]. It has been further hypothesized that these free radicals cause lung tissue to deteriorate during preservation. On the basis of this hypothesis, many free radical scavengers have been investigated as possible agents to help maintain the preserved lung [2–4]. EPC-K1 is a new compound of L-ascorbic acid and {alpha}-tocopherol that has characteristics of a hydroxyl radical scavenger [5] and an inhibitor of phospholipase A2 [6]. Moreover, EPC-K1 is an amphipathic compound that is soluble in both water and lipid, so it may be administered intravenously and is rapidly absorbed. Studies of EPC-K1 have shown it ameliorates reperfusion injury in brain [7], heart [8], liver [9], and lung [10], and has antiinflammatory effects in the setting of uveitis [11]. The present study was designed to determine its effectiveness in improving lung preservation.

Group 3 lungs exhibited satisfactory function in terms of all indices: gas exchange, peak airway pressure, and pulmonary arterial pressure. Group 2 lungs showed severe edema after 120 minutes of reperfusion, and the wet–dry weight ratio in this group was significantly higher than that in group 3. The serum LPO levels, which reflect injury produced by free radicals during reperfusion, were also significantly lower in group 2 than in group 3. However, the lung tissue LPO levels did not change during preservation in either group and there were no significant differences between the two groups. These results indicate that EPC-K1 did not influence lipid peroxidation during preservation but did suppress it on reperfusion. It is unlikely that the residual flush solution in the lung influenced the succeeding reperfusion in some way, because the concentration of EPC-K1 in the perfusate at 0 minute of assessment was below the measurable range (data not shown). Some authors have found evidence of lipid peroxidation of lung tissue occurring during preservation, as shown by the assay of thiobarbituric acid–reacting substances [4, 19, 20], but the value obtained by the thiobarbituric acid method and the amount of LPO were not equimolar [21]. The methylene blue method we used is a simple and sensitive colorimetric method, and moreover, the value obtained by this method and the amount of LPO were equimolar [16].

Other metabolic changes occurring during ischemia-reperfusion have been reported, such as an increase in the phospholipase A2 activity [22, 23]. The activation of phospholipase A2 is mainly responsible for the arachidonate release that precedes the formation of prostaglandin, thromboxane, and prostacyclin [24]. Furthermore, an increase in the level of thromboxane B2, the stable metabolite of thromboxane A2, after ischemia-reperfusion has been reported and found to contribute to the development of pulmonary hypertension in the setting of ischemia-reperfusion injury [25]. Similarly, Kida and associates [10] reported that EPC-K1 attenuated 60-minute warm ischemia reperfusion injury and suppressed the formation of leukotriene C4 and thromboxane B2, both in bronchoalveolar lavage fluid and in blood used in reperfusion, resulting in the suppression of pulmonary vascular resistance.

Our data indicate that the effect of EPC-K1 on ischemia is produced not only by its radical scavenging property but also by its inhibition of phospholipase A2, and the latter effect may play an important role in protecting the lung during preservation. Hence the drug is beneficial for lung preservation and may be superior to single inhibitory agents.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
We thank Tetsuo Kawakami for superb technical assistance and Toshiharu Tsuboi for kindly providing the EPC-K1.


   Footnotes
Top
 Footnotes
Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Address rerint requests to Dr Shimizu, Second Department of Surgery, Okayama University School of Medicine, 2-5-1 Shikata-cho, Okayama, 700, Japan


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

  1. Kirk AJB, Colquhoun IW, Dark JH. Lung preservation: a review of current practice and future directions. Ann Thorac Surg 1993;56:990–1000.[Abstract]
  2. Lambert CJ, Egan TM. Optimal timing of administration of a free radical scavenger in lung preservation. Transplantation 1992;54:205–9.[Medline]
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  6. Kuribayashi Y, Yoshida K, Sakaue T, Okumura A. In vitro studies on the influence of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6yl-hydrogen phosphate] potassium salt on lipid peroxidation and phospholipase a2 activity. Arzneimettelforschung 1992;42:1072–4.
  7. Kuribayashi Y, Naritomi H, Sasaki M, Sawada T. Effect of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6yl-hydrogen phosphate] potassium salt on cerebral energy state and consciousness recovery following transient forebrain ischemia in gerbils. Arzneimettelforschung 1994;44:995–8.
  8. Tanemoto K, Sakagami K, Orita K. Benefical effect of EPC-K1 on the survival of warm ischemic damaged graft in rat cardiac transplantation. Acta Med Okayama 1993;47:121–7.
  9. Yagi T, Sakagami K, Nakagawa H, Takaishi Y, Orita K. A newly developed hydroxyl radical scavenger, EPC-K1, can improve the survival of swine warm ischemia-damaged transplanted liver grafts. Transplant Int 1992;5:420–3.
  10. Kida T. The effect of EPC on warm ischemia-reperfusion injury in lung transplantation. Jpn J Transplant 1992;27:15–25.
  11. Herbort CP, Okumura A, Mochizuki M. Immunopharmacological analysis of endotoxin-induced uveitis in the rat. Exp Eye Res 1989;48:693–705.[Medline]
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  15. Date H, Matsumura A, Manchester JK, et al. Evaluation of lung metabolism during successful twenty-four-hour canine lung preservation. J Thorac Cardiovasc Surg 1993;105:480–91.[Abstract]
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  17. Puskas JD, Oka T, Mayer E, et al. Hemodilution reduces early reperfusion injury in an ex vivo rabbit lung preservation model. Ann Thorac Surg 1994;57:731–5.[Abstract]
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  20. 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]
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  22. Cosenza CA, Cramer DV, Cunneen SA, Tuso PJ, Wang HK, Makowka L. Protective effect of the lazaroid U74006F in cold ischemia-reperfusion injury of the liver. Hepatology 1994;19:418–25.[Medline]
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Invited Commentary
Thomas M. Egan
Ann. Thorac. Surg. 1997 63: 959. [Extract] [Full Text]



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