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Right arrow Lung - transplantation

Ann Thorac Surg 2004;78:292-297
© 2004 The Society of Thoracic Surgeons

Original article: general thoracic

Inhaled nitric oxide attenuates apoptosis in ischemia-reperfusion injury of the rabbit lung

Hideki Yamashita, MDa, Shinji Akamine, MDa*, Yorihisa Sumida, MDa, Masao Inoue, MDa, Takahiro Sawada, MDa, Takeshi Nagayasu, MDa, Tadayuki Oka, MDa

a Department of Translational Medical Sciences, Division of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

Accepted for publication December 2, 2003.

* Address reprint requests to Dr Akamine, Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki, 852-8501 Japan
e-mail: shinji{at}net.nagasaki-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Lung ischemia-reperfusion injury occurs after lung transplantation and various clinical procedures. Recently, apoptosis was reported to be induced after ischemia-reperfusion. We investigated the effects of inhaled nitric oxide (NO) on lung ischemia-reperfusion and apoptosis after ischemia-reperfusion.

METHODS: As a control group, the left pulmonary hilum of Japanese white rabbits (n = 10) was occluded for 120 minutes and reperfused for 120 minutes. In the inhaled NO group (n = 10), 20 parts per million nitric oxide was inhaled during reperfusion. The sham-operated group was ligated at the right hilum and perfused by the left lung only for 120 minutes. The mean pulmonary arterial pressures and PaO2 were measured during reperfusion. The wet-to-dry weight ratio of the left lower lobe of the lung was calculated. The number of apoptotic cells was estimated using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) technique. The TUNEL staining for a time course study was done using 15 control animals that were killed by exsanguination at 15, 30, and 60 minutes after reperfusion.

RESULTS: After 120 minutes of reperfusion, the mean pulmonary arterial pressures in the control group and in the inhaled NO group were 23.0 ± 3.2 mm Hg and 13.6 ± 2.4 mm Hg, respectively (p < 0.01). At the same time point, the PaO2 in the control group and in the inhaled NO group were 46.1 ± 15.9 mm Hg and 88.1 ± 14.7 mm Hg, respectively (p < 0.01). The wet-to-dry weight ratios in the control group and in the inhaled NO group were 0.856 ± 0.024 and 0.808 ± 0.006, respectively (p < 0.01). Apoptotic cells appeared in the early phase of reperfusion (after 15 minutes' reperfusion). The number of apoptotic cells was significantly lower in the inhaled group than in the control group after 120 minutes' reperfusion (1.76% versus 2.87%, p < 0.01).

CONCLUSIONS: Our results suggest that the inhaled NO prevents lung ischemia-reperfusion injury and attenuates apoptosis after reperfusion in the rabbit lung.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Lung ischemia-reperfusion injury remains one of the major problems in lung transplantation. Lung ischemia-reperfusion injury leads to increased microvascular permeability, sequestration of polymorphonuclear neutrophils in the lung, and dysfunction of the pulmonary alveolar endothelium. Previous studies reported that administering exogenous nitric oxide (NO) or NO donors reduces ischemia-reperfusion injury [1, 2]. Nitric oxide was reported to have various physiologic effects, such as vasodilation [3, 4], reduction of platelet aggregation [5], and leukocyte adhesion [6]. Nitric oxide seems to prevent ischemia-reperfusion injury through these effects, but the actual mechanisms remain unknown. Although apoptosis has been identified as an important component of cell death during ischemia-reperfusion injury in heart [7–9], kidney [10], liver [11, 12], and brain [13, 14], the effect of apoptosis on ischemia-reperfusion injury in lung and the effects of inhaled NO on apoptosis remain to be elucidated. The aim of this study is to investigate whether apoptosis is induced after ischemia-reperfusion injury in lung, and the influence of inhaled NO on apoptosis.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Experimental procedure
Japanese white rabbits (2.5 to 3.0 kg) were premedicated with atropine sulfate (0.1 mg/kg) and ketamine hydrochroride (30 mg/kg), and anesthetized using intravenous sodium pentobarbital (20 mg/kg). A cervical tracheotomy was performed, and an endotracheal tube inserted. Anesthesia was maintained using intravenous sodium pentobarbital (10 mg/kg). The animals were ventilated with room air using a respirator (Harvard Rodent Ventilator Model 683; Harvard Apparatus, Tokyo, Japan) with a tidal volume of 10 mL/kg and a respiratory rate of 30 breaths per minutes.

After a median sternotomy, thymectomy was performed, and then bilateral pleura were opened to take out the intermediate lobes of the lungs for prereperfusion lung specimens. Each pulmonary hilum was carefully dissected, and atraumatically encircled with silicon tape. Heparin (500 U/kg) was administrated into an auricular vein of an ear. The pulmonary artery pressure (PAP) monitoring catheter was inserted through the right ventricle into the trunk of the pulmonary artery. An 18-gauge catheter was inserted through a 5-0 Prolene (Ethicon, Somerville, New Jersey) pursestring suture into the right ventricular outflow tract and advanced into the proximal pulmonary artery. Also an 18-gauge catheter was placed in the right femoral artery to monitor systemic blood pressure and to collect arterial blood for arterial blood gas measurements.

Thirty rabbits were divided into three groups (n = 10 for each group). The sham-operated group (sham group) underwent tracheotomy and sternotomy for exposure of the pulmonary hilum for 120 minutes, and then was ligated at the right hilum and perfused by the left lung only for 120 minutes to collect data. The control group was clamped at the left pulmonary hilum by a hemostat for 120 minutes, and the tidal volume of the ventilator was readjusted to 5 mL/kg. After 120 minutes, the left hilum was declamped, and the right hilum was ligated. The left lung was reperfused for 120 minutes, and then the animals were killed by exsanguinations. To obtain the specimens for terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining for a time course study, another 15 control animals were killed by exsanguination at 15, 30, and 60 minutes, five animals each time, after reperfusion. The NO inhalation group received a continuous NO inhalation throughout the reperfusion period. Nitric oxide was fed into the inspiratory limb of the ventilator circuit from a source containing 800 parts per million (ppm) NO in nitrogen (FOS-H; Fukuokasanso, Fukuoka, Japan) with the use of a low-flow flowmeter. The point of entry was sited as close to the lung as possible to minimize the duration of NO mixing with atmospheric oxygen. The air/NO mixture was sampled continuously from a port situated immediately proximal to the lung by a chemiluminescent monitor, which measured and displayed the final concentrations of NO (NO Gas Monitor Model TM-100; Taiyotoyosanso, Osaka, Japan). The final concentrations of nitric oxide were maintained between 19 and 21 ppm.

All animals were approved by the Nagasaki University Animal Care and Use committee and received humane care in accordance with the "Guide for the Care and Use of Laboratory Animals" (National Institutes of Health publication 85-23, revised 1985.

Hemodynamics and arterial blood gas measurement
Systolic, diastolic, and mean pulmonary arterial pressures were recorded with pressure transducers on an electrical recorder and data were taken at prereperfusion, and the time of 0, 5, 15, 30, 90, and 120 minutes after reperfusion. Arterial blood samples were also collected from the arterial line, and these samples were used for blood gas analysis with an analyzer.

Lung wet-to-dry weight ratio
The severity of pulmonary edema was assessed by the wet-to-dry weight ratio of the lung. The left upper lobe was weighed and then dried to a constant weight at 60°C for 72 hours in an oven. The wet-to-dry weight ratio was calculated as follows:

Hematoxylin & Eosin staining
After 2 hours of reperfusion, the inferior segments of left lower lung lobes were fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) pH 7.4, at 4°C overnight and embedded in paraffin using standard procedures. The paraffin-embedded sections (5 µm) were cut onto silane-coated glass slides and dewaxed in a routine manner. The sections were later stained with hematoxylin & eosin (HE) and used for histologic evaluation of tissue damage.

TUNEL staining
To identify nuclei with DNA strand breaks at the cellular level, TUNEL was performed according to the methods of Gavrieli and associates [15] with a slight modification. Briefly, paraffin-embedded sections (5 µm) were cut onto silane-coated glass slides and dewaxed in a routine manner. After washing with PBS, the sections were treated with 0.1 µg/ml proteinase K in PBS at 37°C for 15 minutes. The sections were then rinsed once with deionized distilled water and incubated with TdT buffer (25 mmol/L Tris-HCL buffer, pH 6.6, containing 0.2 mol/L potassium cacodylate and 0.25 mg/ml BSA) alone at room temperature (RT) for 30 minutes. After incubation, the slides were reacted with 0.1 U/µl TdT dissolved in TdT buffer supplemented with 1.0 nmol/L Dig-11- dUTP, 20 µmol/L dATP, 1.5 mmol/L CoCL2, and 0.1 mmol/L dithiothreitol at 37°C for 3 hours. The reaction was terminated by washing with 50 mmol/L Tris–HCL buffer, pH 7.4, for 15 minutes. Endogenous peroxidase activity was inhibited by immersing the slides in 0.3% H2O2 in methanol at RT for 15 minutes. The signals were detected immunohistochemically with HRP-conjugated sheep anti-Dig antibody. Paired tissue sections from each lung were stained with TUNEL and HE. Twenty fields of each lung, which were observed under a microscope (magnification, X400), were randomly selected in each section to count the number of HE-stained and TUNEL-positive apoptotic cells. The number of apoptotic cells was expressed as apoptotic cells per 1000 total cells in each section.

Statistical analysis
All results are presented as mean ± SD. Differences among 3 groups at the same reperfusion interval were compared by the one-way ANOVA (StatView Graphics, Abacus Concepts Inc., Berkeley, CA). All tests were two–tailed and a p value of less than 0.05 was considered to be significant.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
All experiments were technically successful and the treated animals remained stable. The core temperature and acid base status of the animals did not vary significantly during the experiments.

Hemodynamics and oxygenation capacity
Time-dependent changes in mean PAP of each group are shown in Figure 1. The mean PAP was significantly increased in the control group compared with that of the sham group. Inhaled NO during reperfusion attenuated PAP elevation significantly. Nitric oxide remained effective throughout the 120 minutes of reperfusion. At the end of the reperfusion period, the mean PAP was 23.0 ± 3.2 mm Hg in the control group and 13.6 ± 2.4 mm Hg in the inhaled NO group (p < 0.01).



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  		Fig 1. Mean pulmonary arterial pressure. Data are shown as mean ± SD (*p < 0.05 versus control group). Circles = sham; squares = controls; diamonds = nitric oxide inhalation. (min. = minutes; pre = prereperfusion.)

 
Time-dependent changes in the femoral arterial oxygen tension (PaO2) of each group are compared in Figure 2. Oxygenation in the control group was significantly lower during reperfusion than that of the sham group. The control group and the inhaled NO group showed a time-dependent decline in PaO2 after reperfusion. However, inhaled NO attenuated the deterioration of oxygenation after 120 minutes of reperfusion (46.1 ± 15.9 mm Hg versus 88.1 ± 14.7 mm Hg, p < 0.01).



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  		Fig 2. Arterial oxygen tension (PaO2). Data are shown as mean ± SD (*p < 0.05 versus control group). Circles = sham; squares = controls; diamonds = nitric oxide inhalation. (min. = minutes; pre = prereperfusion.)

 
Lung wet-to-dry weight ratio
The wet-to-dry weight ratio increased in rabbits receiving ischemia-reperfusion, compared with that of the sham group (Fig 3). Inhaled NO attenuated the increase in this ratio (0.808 ± 0.006 versus 0.856 ± 0.024, respectively; p < 0.01).



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  		Fig 3. Lung wet-to-dry weight ratio after 120 minutes of reperfusion. Data are shown as mean ± SD. (NO = nitric oxide.)

 
Histologic findings
The appearance of TUNEL-positive cells after ischemia-reperfusion is demonstrated in Figure 4. Several TUNEL-positive cells at a field of 1,000 cells were detectable before reperfusion. The TUNEL-positive cells increased significantly after 15 minutes of reperfusion. No difference was observed in the number of TUNEL-positive cells after 15, 30, 60, and 120 minutes of reperfusion.



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  		Fig 4. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining after ischemia-reperfusion: (a) prereperfusion; (b) 15 minutes after reperfusion; (c) 30 minutes after reperfusion; (d) 60 minutes after reperfusion; (e) 120 minutes after reperfusion; (f) quantification of TUNEL-positive cells at prereperfusion (pre) or after 15, 30, 60, and 120 minutes of reperfusion. Date are shown as mean ± SD (*p < 0.05 versus prereperfusion).

 
Histologic examinations of HE-stained sections showed that ischemia-reperfusion caused edema, hemorrhage, an increase in the thickness of alveolar walls, and an infiltration of inflammatory cells into alveolar spaces (Fig 5, a–c). Inhaled NO attenuated these inflammatory changes and preserved the alveolar structures. In Figure 5, d–f, TUNEL staining of each group is shown after 120 minutes of reperfusion. Several TUNEL-positive cells at a field of 1,000 cells were observed in the sham group. The control group showed significantly increased TUNEL-positive cells, four times that of the sham group (2.87% ± 0.78% versus 0.68% ± 0.11%, respectively; p < 0.01). Inhaled NO during reperfusion attenuated remarkably the increase of TUNEL-positive cells in ischemia-reperfusion (2.87% ± 0.78% versus 1.76% ± 0.49%, respectively; p < 0.01; Fig 6).



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  		Fig 5. Hematoxylin & eosin (HE) staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) staining after 120 minutes of reperfusion. (a–c) HE staining; (d–f) TUNEL staining. (a) and (d) are the sham group; (b) and (e) are the control group; (c) and (f) are the inhaled nitric oxide group.

 


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  		Fig 6. Quantification of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL)-positive cells after 120 minutes of reperfusion. Data are shown as mean ± SD. Inhaled nitric oxide (NO) reduced the increase in TUNEL-positive cells compared with controls.

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In 1980, Furchgott and associates [16] described that the relaxation effect of acetylcholine on smooth muscle cells was endothelium-dependent. In 1987, two independent groups identified this "endothelium-derived relaxing factor" as NO or a related compound [3, 4]. Nitric oxide is synthesized by NO synthase (NOS) through the conversion of L-arginine to L-citrulline. At present, three different NOS isoforms have been identified. Neural NOS (nNOS) is distributed primarily in the central nervous system, whereas endothelial NOS (eNOS) is expressed in vascular endothelial cells. The isoforms nNOS and eNOS are Ca2+/calmodulin-dependent isoforms. Nitric oxide produced by eNOS plays a large role in the regulation of vascular tonus [3, 4], and has a cytoprotective effect due to the inhibition of platelet aggregation [5] and leukocyte adhesion [6]. On the other hand, a third NOS isoform, inducible NOS (iNOS), is a Ca2+-independent isoform and is not expressed in the normal state. The iNOS isoform is regulated at the transcriptional level by cytokines and bacterial endotoxin, and produces excess NO automatically. Excess NO derived from iNOS is thought to be injurious for many tissues. In this way, NO has different functions in the tissue injuries.

In the rat lung ischemia-reperfusion injury, the activity of iNOS is elevated and eNOS activity is decreased owing to endothelial cell damage [17]. Tissue injury from NO overproduction is thought to take place, particularly in an oxidant-rich environment, due to the formation of toxic peroxynitrite [18]. This overproduction may be a cause of lung ischemia-reperfusion injury. Furthermore, NO has cytotoxic effects to inhibit DNA synthesis and to impair mitochondrial function [19]. However, another study reported that administering exogenous NO or NO donors reduced lung ischemia-reperfusion injury [20]. Therefore, in regard to lung ischemia-reperfusion, it is not clear whether endogenous NO is protective or injurious. In this study, we investigated whether NO inhalation influences lung ischemia-reperfusion injury using Japanese white rabbits as a model. Our results showed that NO inhalation suppresses the elevation of mean PAP, the deterioration of PaO2, and the progression of pulmonary edema. These results suggest that NO reduces tissue injury in lung ischemia-reperfusion.

Recently, apoptosis was reported to be induced after ischemia-reperfusion in several organs. Some studies [21–23] have demonstrated that myocardial ischemia-reperfusion results in apoptotic cell death, and that the reduction of myocardial cells by apoptosis degraded cardiac function in ischemia-reperfusion. These findings suggest that the reduction of apoptosis after ischemia-reperfusion may prevent ischemia-reperfusion injury. Wang and associates [24] reported that ischemic preconditioning attenuates myocardial apoptosis and neutrophil accumulation. In ischemia-reperfusion injury of the kidney, apoptosis of tubular epithelial cells was induced through the Fas system [8, 25], and the administration of the antiapoptotic agent ZVAD-fmk (a caspase inhibitor) at the time of reperfusion prevents the early onset of renal apoptosis, inflammation, and tissue injury [26]. In lung ischemia-reperfusion injury and apoptosis, only a few studies have been reported. Stammberger and associates [27] reported that apoptosis was induced in lung ischemia-reperfusion injury. They found that the number of apoptotic pneumocytes did not elevate in lungs stored for 18 hours and fixed without reperfusion, but apoptotic pneumocytes appeared at 2 hours after reperfusion. Our study indicates that apoptosis in rabbit lung ischemia-reperfusion injury is induced very early after reperfusion. Additionally, we observed that inhaled NO reduced apoptosis in the lung after ischemia-reperfusion. These findings suggest that the reduction of apoptosis is one of mechanisms of inhaled NO in preventing the effects in lung ischemia-reperfusion injury.

The role of NO in modulating apoptosis has been controversial. Some have reported that NO potentiates apoptosis [28], whereas others [29, 30] have observed that NO inhibited apoptosis. In vitro studies with cultured macrophages and smooth muscle cells showed that exogenous NO and its reactive oxidant, peroxynitrite, directly induce DNA strand breaks [31, 32]. Preexposure of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP) to rat hepatocytes induced the expression of heat shock protein 70, which correlated with the protection of hepatocytes from apoptosis induced by tumor necrosis factor-{alpha} (TNF-{alpha}) [33]. In human umbilical venous endothelial cells, NO prevents the TNF-{alpha}–induced cell death signal through the inhibition of cysteine protease activation [34]. These differences may be attributed to the concentrations of NO used, the redox status of the cells, the cell type, and the context of the cell.

In conclusion, we demonstrated that inhaled NO prevents lung ischemia-reperfusion injury in rabbit lung models. Apoptosis is induced at the very early phase after lung ischemia-reperfusion, and inhaled NO attenuates apoptosis after lung ischemia-reperfusion. These results suggest that the effect of NO in lung ischemia-reperfusion injury may be derived from a reduction of apoptosis.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors gratefully acknowledge Prof Takehiko Koji, Nagasaki University Graduate School of Biomedical Sciences, for critical comments and useful suggestions.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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