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Eur J Cardiothorac Surg 2007;32:791-795. doi:10.1016/j.ejcts.2007.07.017
Copyright © 2007, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Right arrow Lung - transplantation

Addition of a neutrophil elastase inhibitor to the organ flushing solution decreases lung reperfusion injury in rat lung transplantation

Hideaki Mori*, Itaru Nagahiro, Tomohiko Osaragi, Kazutoshi Kotani, Hidehiro Nakanishi, Yoshifumi Sano, Hiroshi Date, Nobuyoshi Shimizu

Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama City, Japan

Received 7 March 2007; received in revised form 7 July 2007; accepted 11 July 2007.

* Corresponding author. Address: Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikatacho, Okayama Prefecture, Okayama City 700-8558, Japan. Tel.: +81 86 235 7265; fax: +81 86 235 7269. (Email: hmori-ths{at}umin.ac.jp).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Background: Neutrophil elastase plays an important role in ischemia–reperfusion injury. We hypothesized that the addition of sivelestat, a specific neutrophil elastase inhibitor, to the organ flushing solution would decrease reperfusion injury in a rat single left-lung transplant model. Methods: All donor lungs were flushed with 25 ml low-potassium dextran–glucose solution and stored for 16 h at 4 °C. Rats were divided into three experimental groups (n = 10) that received donor lungs washed in either normal flushing solution (group 1), or flushing solution containing 20 mg sivelestat (group 2) or 40 mg sivelestat (group 3). Graft function was assessed 48 h after reperfusion using five measurements: isolated graft oxygenation, wet/dry ratio, peak airway pressure, tissue myeloperoxidase activity, and serum lipid peroxides level. Histological examination of lung grafts was also performed. Results: Group 3 showed better oxygenation (groups 1, 2, and 3: 133.9 ± 113.5, 254.0 ± 84.6, and 378.7 ± 77.6 mmHg, respectively; p < 0.0001 vs group 1, p = 0.0052 vs group 2), lower peak airway pressure (groups 1, 2, and 3: 28.7 ± 6.1, 26.0 ± 5.8, and 21.5 ± 5.3 mmHg, respectively; p = 0.0385 vs group 1), lower wet/dry ratio (groups 1, 2, and 3: 6.74 ± 0.78, 5.77 ± 0.52, and 4.90 ± 0.16, respectively; p = 0.0010 vs group 1), and lower myeloperoxidase activity (groups 1, 2, and 3: 0.304 ± 0.081, 0.178 ± 0.053, and 0.106 ± 0.029 {Delta}OD/mg/min, respectively; p < 0.0001 vs group 1, p = 0.0319 vs group 2). No significant differences in arterial PaCO2 and serum lipid peroxide levels were observed between the three groups. Conclusions: Addition of sivelestat to the organ flushing solution ameliorated ischemia–reperfusion injury in a lung transplant model.

Key Words: Ischemia/reperfusion • Leukocytes • Lung transplantation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Although lung transplantation has become an established therapeutic option for end-stage pulmonary disease, early graft dysfunction remains a life-threatening complication [1]. The causes of early graft dysfunction are mostly insufficient lung protection and direct cell injury originating from ischemia–reperfusion injury. The pathogenic changes that occur during ischemia–reperfusion injury following lung transplantation are similar to those of acute lung injury [2]. Activated neutrophils play an important role in acute lung injury through the production of superoxide radicals and release of chemical mediators and arachidonic acid metabolites [3]. It is well known that neutrophil elastase is released from activated neutrophils, directly causing tissue injury, and may also amplify inflammatory responses in acute lung injury [4,5]. While inhibition of neutrophil elastase has been reported to reduce acute lung injury and ischemia–reperfusion injury in both the liver [6] and heart [7], few reports have examined the effects of neutrophil elastase inhibitors on lung reperfusion injury [8]. In this study we hypothesized that the addition of the specific neutrophil elastase inhibitor sivelestat to the lung flush preservation solution would ameliorate ischemia–reperfusion injury.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1 Sivelestat sodium hydrate
Sivelestat, sodium N-{2-[4-(2,2-dimethylpropionyloxy)phenylsulfonylamino]benzoyl}aminoacetate tetrahydrate (molecular weight 528.51) was purchased from Ono Pharmaceutical Co., Ltd. (Osaka, Japan). Sivelestat sodium hydrate (1.6 mg/ml) was dissolved in 100 ml of low-potassium dextran–glucose (LPDG) solution at room temperature, and stored at 4 °C. The resultant solution was colorless and indistinguishable from standard LPDG.

2.2 Rat left single-lung transplantation model
Inbred male Sprague–Dawley rats weighing 230–280 g (Charles River Japan Inc., Osaka, Japan) were used in all experiments. All animals received humane care in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996. The study protocol was approved by animal research control committee of Okayama University.

2.2.1 Organ retrieval procedure
The study was conducted in a randomized, blinded fashion. Animals were anesthetized by the intraperitoneal administration of 50 mg sodium pentobarbital (Nembutal®; Dainippon Pharmaceutical Co., Osaka, Japan). Animals were then intubated through a tracheostomy with a 14-gauge intravenous catheter, connected to a volume-controlled ventilator (Harvard Rodent Ventilator, model 683; Harvard Apparatus Co., Inc., South Natick, Mass., USA), and ventilated with room air at a respiratory rate of 60 breaths/min, with a tidal volume of 10 ml/kg and a positive end-expiratory pressure of 0.5 cmH2O. A median laparosternotomy was then performed, with 300 IU heparin (Heparin sodium injection-N ‘Shimizu’; Ajinomoto Pharma Co., Ltd., Tokyo, Japan) injected into the inferior vena cava. For retrieval of the heart–lung block, the inferior vena cava was incised, the left atrial appendage truncated, and a 14-gauge cannula placed through a right ventricular outflow tractotomy into the main pulmonary artery. The lungs were flushed through this cannula with 25 ml LPDG with or without sivelestat at 4 °C delivered from a height of 25 cm. Immediately after flushing of the lungs, the endotracheal tube was clamped to keep the lungs inflated for the duration of storage, and the heart–lung block excised. Care was taken to maintain hypothermic conditions, during which cuffs prepared from a 14-gauge cannula were placed into the pulmonary artery, pulmonary vein, and main bronchus. In each case the vessel or bronchus was drawn through the center of the cuff, everted circumferentially around it, and secured with a 7-0 polypropylene ligature. Each lung was then placed into 25 ml LPDG solution for 16 h at 4 °C.

2.2.2 Transplantation procedure
Age-, sex-, strain-, and weight-matched recipient animals were anesthetized with halothane, premedicated with the intramuscular administration of 50 mg ketamine hydrochloride (Veterinary Ketalar® 50; Sankyo Lifetech Co., Ltd., Tokyo, Japan) and 0.1 mg atropine (Atropine Sulfate Injection; Fuso Pharmaceutical Industries, Ltd., Osaka, Japan). Animals were intubated orotracheally, maintained under general anesthesia with a mixture of halothane and oxygen, and ventilated in a similar fashion as described for donor animals. Orthotopic left lung transplantations were performed using a modification of the cuff technique as described by Mizuta et al. [9]. A left-sided thoracotomy was performed through the third intercostal space. The left hilum was dissected, and the pulmonary artery, pulmonary vein, and the left main bronchus identified and isolated. All three structures were clamped with microsurgical aneurysm clamps (Sugita aneurysm Clip; Mizuho Co., Ltd., Tokyo, Japan), incised on their anterior aspects, and the donor cuffs inserted and held in place with 6-0 silk ties. The chest was closed, and a chest tube left in place until after removal of the tracheal tube. Animals were placed in a cage, and supplied food and water ad libitum. All transplantations were performed by a single surgeon using an operating microscope (Leica M715; Leica Microsystems (Schweiz) AG, Heerbrugg, Switzerland).

2.3 Assessment
At 48 h after reperfusion, all animals were anesthetized with pentobarbital (10 mg/kg intraperitoneally), intubated, and ventilated as described for donor animals. For measurement of peak airway pressure, a three-way tap was inserted between the endotracheal tube and the ventilator circuit and connected to a pressure transducer. Access was gained to the right pulmonary hilum by median laparosternotomy. The ventilator was set at a 100% fraction of inspired oxygen, a tidal volume of 5 ml/kg, a respiratory rate of 100 per min, and a positive end-expiratory pressure of 0.5 cmH2O. The right main pulmonary artery and main bronchus were occluded with a 3-0 silk tie. After 5 min, blood was sampled under direct vision using a needle inserted into the ascending aorta for blood gas measurement and serum lipid peroxide assay. Peak airway pressure was measured and monitored continuously. After exsanguination, the graft was extracted from the thorax.

2.3.1 Tissue samples
Excised lungs were divided into thirds. The superior third was used for wet/dry weight ratio, the middle third was processed for myeloperoxidase (MPO) analysis (snap frozen in liquid nitrogen and stored at –80 °C), and the inferior third was used for histological examination.

2.3.2 Wet/dry ratio
Specimens for wet/dry ratio calculation were weighed on pieces of tin foil and then placed in an 80 °C oven for 72 h and then reweighed. The wet/dry ratio = (total wet weight – weight of tin foil)/(total dry weight – weight of tin foil).

2.3.3 MPO activity assay
MPO activity in lung tissues was measured as previously described [10]. Lung tissue samples, stored at –80 °C until assay, were weighed, homogenized, and sonicated in 0.5% hexadecyltrimethylammonium bromide (HTAB) (Sigma Chemical, St. Louis, MO, USA) in 50 mmol/l phosphate buffer (pH 6.0, 5.0 ml HTAB/g tissue). Homogenates were centrifuged at 10000 x g at 4 °C for 15 min. Supernatants were decanted and 0.1 ml aliquots mixed with 2.9 ml 50 mmol/l potassium phosphate buffer (pH 6.0) containing o-dianisidine hydrochloride (0.167 mg/ml; Sigma Chemical, St. Louis, MO, USA) and 0.0005% hydrogen peroxide. Absorbance change at 460 nm was recorded with spectrophotometer (U-2001, Hitachi, Tokyo, Japan) at 5 and 20 min at room temperature. Color development from 5 to 20 min was linear. Enzyme activity was defined as the amount of MPO that produced an absorbance change of 1.0 optical density unit per min per mg of tissue protein at room temperature ({Delta}OD/mg/min).

2.3.4 Serum lipid peroxide assay
Blood samples were centrifuged at 3000 x g for 10 min and stored at 4 °C until measurement. Serum lipid peroxide assays were performed using the method of Ohishi et al. [11].

2.3.5 Histological analysis
Specimens were fixed in 10% formalin, dehydrated, embedded in paraffin, cut into 5 µm sections, and mounted. Following deparaffinization, sections were stained with hematoxylin and eosin. A pathologist blinded to the study analyzed the slides for signs of hemorrhage, ischemic changes, inflammation, and edema.

2.4 Experimental groups
Experimental groups were designed as follows: group 1 (n = 10) served as control; group 2 (n = 10) had 20 mg sivelestat added to the flushing solution (0.8 mg/ml); and group 3 (n = 10) had 40 mg sivelestat added to the flushing solution (1.6 mg/ml).

2.5 Statistical analysis
All data are expressed as mean value ± standard deviation. Groups were compared using analysis of variance with the Scheffe multiple comparison method. Differences are considered significant when p was less than 0.05. The StatView® J 5.0 (SAS Institute Inc.; Cary, North Carolina, USA) software package was used for all statistical analyses.


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
One recipient in group 1 displayed severe pulmonary edema with aspiration to the contralateral side and died within 24 h after transplantation, and was excluded from analysis.

3.1 Blood gas analysis
In the control group (group 1), arterial PO2 level at oxygenation 48 h after graft reperfusion was low (133.9 ± 113.5 mmHg). Addition of 40 mg sivelestat to the flushing buffer resulted in increased oxygenation compared to controls (group 3: 378.7 ± 77.6 mmHg). Addition of 20 mg sivelestat also improved gas exchange, but to a significantly lesser extent than the addition of 40 mg sivelestat (group 2: 254.0 ± 84.6 mmHg). Arterial PCO2 level was 32.6 ± 12.1 mmHg in group 1, 29.9 ± 13.0 mmHg in group 2, and 32.9 ± 9.4 mmHg in group 3, with the difference between the groups not statistically significant (Fig. 1 ).


Figure 1
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  		Fig. 1. Arterial blood gas analysis. Data shown as the mean ± SD.

 
3.2 Peak airway pressures
Peak airway pressure was 28.7 ± 6.1 mmHg in group 1, 26.0 ± 5.8 mmHg in group 2, and 21.5 ± 5.3 mmHg in group 3, such that the peak airway pressure was significantly lower in group 3 than in group 1. However, there was no significant difference between groups 1 and 2, or between groups 2 and 3 (Fig. 2 ).


Figure 2
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  		Fig. 2. Peak airway pressure. Data shown as the mean ± SD. N.S, not significant.

 
3.3 Wet/dry ratio
Rats that received organs exposed to sivelestat (groups 2 and 3) had lower wet/dry ratios (5.77 ± 0.52 and 4.90 ± 0.16, respectively) than the control group (group 1: 6.74 ± 0.78). However, only the difference between groups 1 and 3 was statistically significant (Fig. 3 ).


Figure 3
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  		Fig. 3. Wet/dry ratio. Data shown as the mean ± SD.

 
3.4 Serum lipid peroxide assay
Serum lipid peroxide level was 0.920 ± 0.444 nmol/ml in group 1. While the addition of sivelestat in groups 2 and 3 led to reduced serum lipid peroxide levels (0.760 ± 0.297 nmol/ml and 0.780 ± 0.239 nmol/ml, respectively), this reduction was not statistically significant (Fig. 4 ).


Figure 4
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  		Fig. 4. Serum lipid peroxides level. Data shown as the mean ± SD.

 
3.5 MPO activity assay
The tissue MPO activity of group 1 was 0.304 ± 0.081 {Delta}OD/mg/min. Addition of 40 mg sivelestat resulted in the significant reduction of MPO activity (group 3: 0.106 ± 0.029 {Delta}OD/mg/min), while the addition of 20 mg sivelestat had a lesser effect on MPO activity (group 2: 0.178 ± 0.053 {Delta}OD/mg/min) (Fig. 5 ).


Figure 5
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  		Fig. 5. MPO activity of lung grafts. Data shown as the mean ± SD. N.S, not significant.

 
3.6 Histological analysis
Histological sections from group 1 rats showed signs of severe congestion and interstitial edema, whereas sections from rats that received lung tissue flushed with sivelestat (groups 2 and 3) showed only moderate congestion and less interstitial edema (Fig. 6 ).


Figure 6
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  		Fig. 6. Hematoxylin and eosin staining of lung grafts. Original magnification, x100.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
In this study, we used a rat single-lung transplantation model of ischemia–reperfusion injury to evaluate the protective effects of sivelestat. We found that the addition of sivelestat to the organ flushing solution resulted in significantly improved oxygenation, peak airway pressure, and wet/dry weight ratios measured after 16 h cold storage and 48 h reperfusion. The use of isogeneic rats meant that we were able to eliminate rejection as a confounding factor in the assessment of transplant outcome.

Several studies have shown that agents such as prostaglandin, vasoactive intestinal peptide, trimetazidine, and melatonin are effective in protecting the lung against ischemia–reperfusion injury [12–14]. Ischemia–reperfusion injury has a complex and multifactorial pathogenesis. Indeed, neutrophil elastase has been implicated in the increased permeability of both vascular endothelial and alveolar epithelial cells that are considered to be profoundly involved in lung edema [4,15,16].

In the normal state, neutrophil elastase activity is inhibited by alpha-1 protease inhibitor, the main circulatory neutrophil inhibitor in vivo [17]. During an acute inflammatory process, lung injury can result from the enhancement of neutrophil elastase activity, accompanied by the inactivation of alpha-1 protease inhibitor due to reactive oxygen species released from neutrophils [18]. Kishima et al. reported that leukocyte depletion or treatment with neutrophil elastase inhibitor during reperfusion reduced alveolar–capillary damage caused by lung ischemia–reperfusion injury in the non-heart-beating donors lung transplantation setting by measuring filtration coefficient [19].

Sivelestat is a new recombinant neutrophil elastase inhibitor with a much lower molecular weight than alpha-1 protease inhibitor, and appears to exert its effect in the microenvironment between neutrophil and tissues, whereas alpha-1 protease inhibitor only incompletely blocks neutrophil-mediated tissue destruction [18,20]. The protective effect of sivelestat may be largely attributable to the specific inhibition of neutrophil elastase activity. As previously reported, while sivelestat inhibits hamster neutrophil elastase activity with a 50% inhibitory concentration (IC50) value of 37 ± 4 nM, it does not inhibit other neutrophil-derived proteases, such as cathepsin G [20]. In both in vitro and in vivo experiments, sivelestat has been found to protect cells, tissues, and organs against damage induced by a variety of processes, including lipopolysaccharide, tumor necrosis factor-alpha, cobra venom factor, acid, and ischemia–reperfusion injury [4,8,21,22].

Based on these reports, we hypothesized that as sivelestat exerts its protective effects through the suppression of neutrophil elastase activity, its presence in graft tissue should result in reduced neutrophil sequestration and lipid peroxidation, lessening edema in the graft, and improving oxygenation. Our results indicated that the addition of sivelestat to the flushing solution did reduce edema formation, enhance oxygenation, and lower neutrophil sequestration. Our findings suggested that while sivelestat showed an inhibitory effect against ischemia–reperfusion injury in a dose-dependent manner, serum lipid peroxide levels were not significantly altered. It is possible that this finding is due to the length of time after reperfusion (48 h) being too long to detect some significant differences between the experimental groups.

Previous studies examining the use of sivelestat in organ protection have used a variety of dose regimens and delivery methods. In clinical lung transplantation, the most immediately relevant means of delivering sivelestat to the graft is via the flushing solution used at the time of harvest. This allows delivery to the specific donor organ. Therefore, we added sivelestat to the flushing solution in our model. As the proper dose of sivelestat has not yet been determined, we decided the dose empirically, based on other models [23]. Further studies will be needed to determine the optimal dosage and appropriate delivery method of sivelestat.

In conclusion, we have shown that sivelestat added to the flushing solution in a rat single-lung transplant model decreased the severity of ischemia–reperfusion injury, as demonstrated by significantly improved oxygenation, peak airway pressure, and post-transplantation pulmonary edema. Our study suggested that sivelestat might be an important adjunct in prolonging ischemic time safely and in decreasing lung ischemia–reperfusion injury.


   Acknowledgments
 
We thank Mr Tetsuo Kawakami for technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

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  5. Kawabata K, Hagio T, Matsumoto S, Nakao S, Orita S, Aze Y, Ohno H. Delayed neutrophil elastase inhibition prevents subsequent progression of acute lung injury induced by endotoxin inhalation in hamsters. Am J Respir Crit Care Med 2000;161:2013-2018.
  6. Yamaguchi Y, Akizuki E, Ichiguchi O, Matsumura F, Goto M, Miyanari N, Mori K, Yamada S, Ogawa M. Neutrophil elastase inhibitor reduces neutrophil chemoattractant production after ischemia–reperfusion in rat liver. Gastroenterology 1997;112:551-560.
  7. Ueno M, Moriyama Y, Toda R, Yotsumoto G, Yamamoto H, Fukumoto Y, Sakasegawa K, Nakamura K, Sakata R. Effect of a neutrophil elastase inhibitor (ONO-5046 Na) on ischemia/reperfusion injury using the left-sided heterotopic canine heart transplantation model. J Heart Lung Transplant 2001;20:889-896.
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