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Ann Thorac Surg 1998;65:913-918
© 1998 The Society of Thoracic Surgeons

Microvascular Permeability of the Non–Heart-Beating Rabbit Lung After Warm Ischemia and Reperfusion: Role of Neutrophil Elastase

Hiroki Kishima, MDaa, Shin-ichi Takeda, MDaa, Shinichiro Miyoshi, MDaa, Akihide Matsumura, MDaa, Masato Minami, MDaa, Tomoki Utsumi, MDaa, Ken-ichi Omori, MDaa, Kazuya Nakahara, MDaa, Hikaru Matsuda, MDaa

a First Department of Surgery, Osaka University Medical School, Osaka, Japan

Accepted for publication October 20, 1997.

Address reprint requests to Dr Takeda, First Department of Surgery, Osaka University Medical School, 2-2 Yamadaoka, Suita Osaka 565, Japan
e-mail: (stakeda{at}surg1.med.osaka-u.ac.jp)


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. The duration of warm ischemia and reperfusion injury is a major limiting factor in the setting of lung transplantation with non–heart-beating donors (NHBD). We hypothesized that reperfusion with neutrophil elastase inhibitor or leukocyte-depleted blood has an inhibitory effect on the ischemia-reperfusion injury of NHBD rabbit lungs.

Methods. To assess the lung injury, we used a perfused rabbit lung model and measured the hemodynamic parameters and filtration coefficient. The rabbit lungs after hypoxic cardiac arrest for 30, 50, and 60 minutes were harvested at room temperature, and ventilated lungs were reperfused for 1 hour at a constant flow (120 mL/min). The group with 60 minutes of warm ischemia and hypoxia was further divided into three groups to determine the effects of leukocyte-depleted reperfusion or neutrophil elastase inhibitor, (1) no other special treatment, (2) reperfusion with leukocyte-depleted blood, and (3) administration of 10 mg of specific neutrophil elastase inhibitor. The lungs reperfused immediately after harvest from the heart-beating donor were regarded as the control.

Results. Sixty minutes of warm ischemia and hypoxia resulted in an increase in filtration coefficient (0.68 ± 0.20 g · min-1 · cm H2O-1 per 100 g) compared with the control values of 0.13 ± 0.03 g · min-1 · cm H2O-1 per 100 g. The increase in filtration coefficient after 60 minutes of warm ischemia and hypoxia in NHBD was remarkably suppressed by leukocyte depletion (0.23 ± 0.07) and by neutrophil elastase inhibitor (0.21 ± 0.08). The shunt fraction and histology results were also near normal.

Conclusions. These results suggested that leukocyte depletion or treatment with neutrophil elastase inhibitor during reperfusion reduces alveolar–capillary damage caused by lung ischemia–reperfusion injury in the NHBD lung transplantation setting. This effect might be mediated by inhibition of neutrophil elastase activity or sequestration, and thus may lead to the increased availability of NHBD lungs.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Despite increasing clinical success in lung transplantation, the scarcity of donor lungs for lung transplantation remains a serious problem. Two alternatives, xenotransplantation and non–heart-beating organ donation, may provide sources for greater allograft availability. In this regard, several investigators have studied non–heart-beating donor (NHBD) lungs after various treatments for transplantation [1–3]. Their results regarding the limit of warm ischemic time are conflicting from 1 to 4 hours. The application of free radical scavenger [2] and the use of preharvest ventilation [3, 4] seem to improve the limit of warm ischemic time in the setting of NHBD lung transplantation.

Acute lung injury attributable to the ischemia and reperfusion has been attributed to oxygen free radicals [5], leukocyte [6], and arachidonic acid metabolites [7]. Synergy between oxygen free radicals and protease has been postulated recently to play an important role in the progression of lung injury, as Kubo and colleagues [8] suggested using endotoxin model. However, no experimental studies have focused on the role of neutrophil elastase and the protease inhibitor on ischemia-reperfusion lung injury with an emphasis on the clinical application in lung transplantation. We therefore designed the present experiments (1) to determine the time course of lung injury of reperfused NHBD lung from the viewpoint of microvascular permeability and (2) to assess the inhibitory effects of a protease inhibitor (ONO-5046, Ono Pharmaceutical, Osaka, Japan) or leukocyte depletion on ischemia-reperfusion injury. To evaluate accurately the damage in the alveolar–capillary permeability, we measured the filtration coefficient (Kf) as well as standard physiologic parameters of isolated perfused lung. Because Kf has been known to represent microvascular permeability, it indicates a particularly sensitive index for the evaluation of the pharmacologic modulation or leukocyte depletion in the warm ischemia and reperfusion.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Lung preparation
Two Japanese white rabbits of either gender weighing 2.42 ± 0.15 kg were prepared for each experiment. One rabbit was anesthetized with 25 mg/kg sodium pentobarbital (Abbot Laboratories, Chicago, IL) and injected intravenously with 700 U/kg of heparin (Shimizu, Tokyo, Japan). After collection of heparinized blood, the second rabbit was anesthetized with 25 mg/kg sodium pentobarbital and anticoagulated with 700 U/kg of sodium heparin. Each animal was intubated through a cervical tracheostomy and ventilated with room air. Respiratory condition was set at a tidal volume of 10 mL/kg and respiratory rate of 25 breaths/min using volume-limited ventilator (model SN-480-7; Shinano Ika, Tokyo, Japan). Positive end-expiratory pressure of 0.5 cm H2O was applied to avoid lung atelectasis. One cannula was placed into the pulmonary artery and another was placed in the aorta for pressure monitoring. Cardiac standstill was then induced followed by transient hypoxic hypertension after the administration of 1 mg of pancuronium bromide (Organon, Boxtel, the Netherlands) and the discontinuation of mechanical ventilation. The cadaver lung was kept securely at room temperature for 30, 50, and 60 minutes for each group and then mechanical ventilation was initiated. The main pulmonary artery was cannulated with a 14F double lumen catheter (Sumitomo, Osaka, Japan) for perfusion (inflow) and pressure monitoring, and the aorta was ligated at its root. Fourteen-gauge catheters were placed in the left ventricle for perfusion (outflow) and in the left atrium for pressure monitoring. The heart–lung block was harvested with the lung inflated at the functional residual capacity level. The preperfusion lung weight was calculated as the difference between the weight of preperfusion heart–lung block and that of the postexperiment block without lung.

Experimental design
Twenty-five lung blocks were divided into six groups according to the warm ischemic and hypoxic (WIH) time (Fig 1). In group 1 (heart-beating donor/control; n = 4), the lung block was isolated from the beating heart and reperfused immediately for 1 hour. In groups 2 to 6, the rabbits were left at room temperature (23 ± 1.5°C; humidity, 45% ± 15%) with deflated lungs for 30 minutes (group 2; n = 4), 50 minutes (group 3; n = 4), and 60 minutes (groups 4 to 6; n = 13), respectively, after cardiac arrest. Under mechanical ventilation, the lung block was isolated and reperfused for 1 hour.



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  		Fig 1. Schematic diagram of the isolated perfusion circuit with a membrane oxygenator. (Paw = airway pressure; Pla = left atrial pressure; Ppa = pulmonary arterial pressure.)

 
The 60-minutes WIH group was further subdivided into three groups (groups 4 to 6): In group 4 (n = 5), no other special treatment was performed. In the leukocyte-depleted group (group 5; n = 4), reperfusion blood was passed through a leukocyte removal filter (Sepacell-R500, Asahi Medical Co, Tokyo, Japan) before a reperfusion experiment. In group 6 (n = 4), 10 mg of ONO-5046 was administered in the reperfusion blood. This dosage was based on the report that the continuous administration of 10 mg · kg-1 · h-1 of ONO-5046 is enough to inhibit the neutrophil elastase activity [9]. Therefore, in our specific model, 10 mg of ONO-5046 was administered to the perfusion blood before reperfusion experiment without a continuous administration during experiment. The concentration of ONO-5046 in the blood was 83.9 ± 11.7 µg/mL before and 84.3 ± 11.6 µg/mL after the experiment.

Perfusion circuit
The perfusion system, schematically represented in Figure 2, was composed of silicone tubing (3 mm inner diameter). Blood was collected and adjusted to a hemoglobin concentration of 8 g/dL with saline solution and primed in the perfusion circuit. Blood from the reservoir was pumped to the lung block through a blood filter (Pall, Kawasumi Kogyo, Tokyo, Japan) and a membrane oxygenator (Silox-S HSO 0.3; Senko Ika, Tokyo, Japan). Blood from the lung block was passively drained into the reservoir, and then the lung block was perfused with a constant flow of 120 mL/min according to the method of Weder and colleagues [10] using a roller pump (Masterflex pump system, Cole-Palmer Instrument Co, Chicago, IL). To deoxygenate and carbonize the perfusion blood, 95% nitrogen and 5% carbon dioxide gases were delivered through a membrane oxygenator.



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  		Fig 2. Sample chart record showing changes in lung weight gain accompanied by left atrial pressure (Pla) elevation. The calibration of the lung weight change was made by placing two 4-g weights on the lung in sequence.

 
The lung block was housed within a warm (38°C) humidified chamber, with its longest dimension in the horizontal plane on a plate suspended from one arm of a balance beam, as we previously described [11]. The other arm of the beam was connected to a force displacement transducer (model TB611T, Nihon Kohden, Tokyo, Japan) for continuous weight measurement after zero calibration. This weighing system was adjusted for a 4-g weight on the lung block of a 2-cm pen deflation (the lower left corner in Fig 3).



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  		Fig 3. Recording of the outflow pressure (Pout) during outflow occlusion. (Ppc0 = pulmonary capillary pressure at the baseline level (Ppa0,Pla0); {Delta}Pla = the pressure gradient between Ppc0 and left atrial pressure.)

 
Measurements
Measurements of pulmonary hemodynamics, gas exchange, and permeability parameters were described in detail in our previous report [11]. Briefly, the mean inflow (Ppa), outflow (Pla) and airway pressures (Paw) were monitored with transducers (models LPU-0.1U,TP-300T, TP-603T, respectively, Nihon Kohden) with Pla kept below 0.5 cm H2O throughout the experiment. The lung was ventilated with room air at a tidal volume of 10 mL/kg, a frequency of 30/min, and the end-expiratory pressure of 0.5 cm H2O. The oxygen and carbon dioxide partial pressures, hemoglobin concentration, and pH were measured with a blood gas analyzer (ABL2, Radiometer, Copenhagen, Denmark). The lung weight changes, vascular pressures, and airway pressure were continuously recorded on a polygraph (WT-685G, Nihon Kohden).

We measured all parameters 1 hour after reperfusion, when the Ppa was stable at less than 40 cm H2O, and when the lung weight was stable (isogravimetric). The partial pressure of alveolar oxygen and intrapulmonary shunt fraction (Qs/QT) were calculated using the standard formula [12]. Thereafter, the outflow pressure was increased in steps by adjusting the height of the reservoir. Consequent changes in Ppa and weight gain rate were recorded (Fig 3). Each step was maintained until the weight gain rate became constant for at least 5 minutes. To obtain the zone 3 condition (Ppa > Pla > Paw), we increased the Pla above the Paw as the first step, as described by Ehrhart and co-workers [13]. The distribution of pulmonary vascular resistance and pulmonary capillary pressure (Ppc) were estimated by the venous occlusion technique described by Hakim and colleagues [14]. After three steps of Pla increase, Ppa and Pla were returned to baseline level (Ppa0, Pla0), and the venous cannula was rapidly occluded for 2 to 3 seconds (Fig 3). The outflow pressure (Pout) increased rapidly by {Delta}Pla, and then a slow component of pressure increase followed. The Pc baseline level (Ppc0) was determined by extrapolating the curve of the slow component back to the time of occlusion.

The hemodynamic parameters were calculated by the following equations, described in detail previously [11].

We plotted the weight gain rate as a function of Ppc. A two-variable linear regression was applied to obtain the filtration coefficient of alveolar capillary membrane (Kf) from the slope of the line relating the weight gain rate and Ppc. Kf is expressed as per 100 g wet lung.

All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication No. 85-23, revised 1985).

Histology
For histologic examination, two additional perfusion experiments were performed in each group to avoid the bias of artificial hydrostatic lung edema during Kf measurement. After 1 hour of reperfusion, the left lung was expanded and fixed with 10% buffered formalin for 2 to 3 days. We took all lobes and examined serial sections of the lobe for each animal. Five-millimeter thick sections of the lungs were embedded in paraffin, sectioned into 3- to 4-µm pieces, and stained with hematoxylin and eosin. The number of neutrophils in the peripheral lung tissue was counted per one visual field at a magnification of x400, and then averaging a total of 10 visual fields for each group as previously reported [8]. The pathologists were blinded to the groups.

Statistics
The data are presented as means ± standard error of mean. Statistical comparisons between groups were made using the multiple range test by Newman-Keuls [15] for significant differences between means. We accepted p values less than 0.05 as significant.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Table 1 shows the hemodynamic and permeability parameter results.


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  		Table 1. Hemodynamic Measurements and Filtration Coefficient 1 Hour After Reperfusion

 
In the groups that underwent WIH for less than 60 minutes (groups 2 and 3), there were no significant differences in the hemodynamic and permeability parameters compared with the control values. Total RT tended to increase with WIH time; a 60% increase occurred in group 3 compared with control values, but the difference did not reach significance. Sixty minutes of WIH (group 4) caused a significant increase in Kf (0.68 ± 0.20 g · min-1 · cm H2O-1 per 100 g) and a Qs/Qt value of 40.2% ± 20.4% compared with control values (Fig 4). The Kf and Qs/Qt values were near normal in group 5 (0.23 ± 0.07 and 5.2 ± 2.7, respectively) and in group 6 (0.21 ± 0.08 and 2.1 ± 1.1).



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  		Fig 4. Filtration coefficient (Kf) in group 4 was significantly higher than in the other groups. (*p < 0.05.) (HBD = heart-beating donor; LD = leukocyte depletion; NEI = neutrophil elastase inhibitor; NHBD = non–heart-beating donor.)

 
Photomicrographs of lung specimens of groups 1, 4, and 6 are shown in Figure 5. In group 4, there were moderate to severe signs of pulmonary edema consisting of interstitial thickening and a high degree of neutrophil infiltration in the lung capillary vessels and interstitium. In contrast, in group 6 there were no features to suggest pulmonary edema, and only slight neutrophil infiltration was observed. The histologic findings of group 6 was similar to that of the control.



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  		Fig 5. Microscopic appearance of the lung 60 minutes after reperfusion (hematoxylin–eosin; original magnification; x400). (A) Group 1, (B) group 4, thickened interstitium and infiltration of neutrophils are noted. (C) group 6, no remarkable change is seen compared with group 1.

 
The number of neutrophils in the lungs per single field at a magnification of x400 is plotted against Kf for all groups (Fig 6). The levels of neutrophils in the lungs of group 2 (42.4 ± 7.9), group 3 (47.5 ± 3.7), and group 4 (72.6 ± 18.2) were significantly (p < 0.005) higher than that of the control group (group 1) (17.6 ± 3.6). The levels of neutrophils of groups 5 (2.3 ± 1.4) and 6 (8.5 ± 3.0) were not significantly different from that of the control group (group 1). The leukocyte removal filter and ONO-5046 treatment suppressed the increase in Kf as well as the neutrophil sequestration in the NHBD rabbit lungs after warm ischemia-reperfusion.



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  		Fig 6. Correlation of neutrophil numbers per one visual field at a magnification of x400 with filtration coefficient of the lung.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Clinical lung transplant programs are designed to harvest donor lungs from brain-dead subjects with intact circulation (ie, heart-beating donors). However, the scarcity of donor lung for lung transplantation has prompted to consider the option of non–heart-beating organ donation as a potential source of allografts. In some parts of the world, such as Japan and China, brain death has never been recognized or accepted officially. In this sense, with the goal of the clinical success in lung transplantation, the pharmacologic control of ischemic and reperfusion lung injury is even more urgent in the setting of NHBD lung transplantation. In the present study, we have set a warm ischemic time around 30 to 90 minutes, including harvesting time, a relatively short time compared with those of the earlier studies [1, 2]. We believe that this experimental schedule best reproduces the clinical conditions in the setting of lung transplantation from NHBD. Ischemic reperfusion injury is characterized by increased pulmonary capillary permeability, resultant pulmonary edema, and acute pulmonary hypertension, all of which are regarded as obstacles to the use of NHBD.

To evaluate accurately the ischemic and reperfusion injury, we estimated the pulmonary vascular permeability by measuring Kf. As we previously reported [11], Kf has been shown to represent the sum of the hydraulic conductivities of the pulmonary capillary membrane, namely the microvascular permeability. The determination of Kf for permeability of the capillary wall relies on the Starling equation: , where Jv is the fluid flux across the microvasculature membrane, Pc and Pt are the microvascular and interstitial fluid pressures, respectively, {pi}c and {pi}t are the plasma and interstitial fluid colloid osmotic pressures, respectively, and {sigma} is the osmotic reflection coefficient for total proteins. If one assumes that {pi}c = {pi}t during Kf measurement, Jv is expressed as an increase in the weight of the lung per minutes ({Delta}Wt/{Delta}time): .

In our experiment, Pc was increased stepwise and {Delta}Wt/{Delta}time was recorded according to the assumption that Kf is not affected by changes in the hematocrit. In the present study using 8 g/dL of hemoglobin, Kf in the control group was in good agreement with other researchers (0.084 to 0.31 g · min-1 · cm H2O-1 per 100 g wet lung) [16, 17]. In addition, we have confirmed that Kf was well correlated with other hemodynamic and gas exchange parameters such as Qs/Qt and RT (data not shown).

The present results showed that deflated rabbit lung had a normal Kf at less than 60 minutes of total WIH time when it was reperfused for 1 hour (group 3). However, Kf increased significantly with lung edema in the group with 60 minutes of WIH (group 4). Our preliminary experiment with a longer WIH induced overwhelming lung injury, which we consider unsuitable to assess pharmacologic intervention. Collectively, our results are in good agreement with previous observations that the tolerance time for warm ischemia of the deflated rabbit lung is at most 2 hours [2, 18].

In the present study, leukocyte depletion in the reperfusion blood significantly reduced the reperfusion injury after about 90 minutes of warm ischemia in the NHBD cadaver lung (group 5). Multiple factors may be involved in the progression of reperfusion injury of the lung. However, the present findings show that neutrophils play a crucial role in ischemia–reperfusion lung injury. Previously, we reported the beneficial effects of leukocyte-depleted cardioplegia and of leukocyte-depleted reperfusion in heart [19] and heart–lung [20] preservation models. Activated neutrophils release neutral protease, superoxide, arachidonic metabolites, and platelet-activating factor. With regard to the pharmacologic modulation, it has been documented that reperfusion lung injury may be attenuated by oxygen free radical scavenger [21], DMTU (hydroxyl radical scavenger) [22], and catalase (hydrogen peroxide scavenger) [23]. However, superoxide has a short half-life and a nonselective reaction. In contrast, neutrophil elastase acts for a long time to decompose proteoglycan and accelerates vascular permeability [24]. In the present study, the neutrophil elastase inhibitor improved the ischemic and reperfusion injury, similar to the leukocyte-depleted reperfusion.

Regarding the mechanism of action, Weiss and colleagues [25] demonstrated that neutrophil elastase directly injured vascular endothelial cells, whereas superoxide action was indirect by inactivating alpha-1-protease inhibitor. Therefore, there is a possibility that neutrophil elastase directly injures the lung capillary vascular endothelium of ischemia–reperfusion lungs. The selective neutrophil elastase inhibitor ONO-5046 is a reversible and competitive inhibitor of neutrophil elastase in humans, rabbits, rats, hamsters, mice, and sheep [8, 9]. This inhibitory action is specific for neutrophil elastase, as it did not inhibit other proteases such as trypsin, thrombin, plasmin, kallikrein, and catepsin G.

However, the effect of this inhibitor on the ischemia–reperfusion lung injury has not been reported to date. In the present study, the neutrophil elastase inhibitor markedly reduced the ischemia–reperfusion injury and resultant pulmonary edema in the NHBD lung models. Taken together, these findings suggest that the effect of oxygen radicals on reperfusion injury may be small, because ONO-5046 does not possess the ability to scavenge reactive oxygen species (S. Matsuoka, Ono Pharmaceutical, Osaka, Japan, personal communication).

Our results have shown that neutrophil elastase plays a major role in ischemia–reperfusion lung injury, indicating that pharmacologic modulation may have a clinical impact on the use of NHBD lungs for transplantation.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
We gratefully acknowledge the generous provision of ONO-5046 by Ono Pharmaceutical, Osaka, Japan.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
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