Ann Thorac Surg 2001;72:1165-1171
© 2001 The Society of Thoracic Surgeons
Original article: general thoracic
Effect of a cyclooxygenase-2 inhibitor, FK3311, in a canine lung transplantation model
Yutaka Sunose, MDa,
Izumi Takeyoshi, MDa,
Hirofumi Tsutsumi, MDa,
Susumu Ohwada, MDa,
Noboru Oriuchi, MDb,
Koshi Matsumoto, MDc,
Yasuo Morishita, MDa
a Second Department of Surgery, Gunma University School of Medicine, Gunma, Japan
b Department of Nuclear Medicine, Gunma University School of Medicine, Gunma, Japan
c Department of Pathology, Nippon Medical School, Kanagawa, Japan
Accepted for publication May 16, 2001.
Address reprint requests to Dr Takeyoshi, Second Department of Surgery, Gunma University School of Medicine, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8511, Japan
e-mail: takeyosi{at}showa.gunma-u.ac.jp
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Abstract
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Background. In the process of ischemia–reperfusion, inflammatory cytokines and arachidonic acid metabolites are released and followed by tissue damage. FK3311 (FK) is a selective cyclooxygenase-2 inhibitor that inhibits conversion of arachidonic acid into thromboxane A2 or prostaglandin I2. We investigated the effects of FK in canine lung transplantation.
Methods. FK3311 was administered in the FK group, and vehicle was injected in the control group. The left lung was orthotopically transplanted after 12-hour preservation in Euro-Collins solution. After reperfusion, the right pulmonary artery and bronchus were ligated, and the animals were observed. Pulmonary gas exchange and hemodynamics were measured, histopathologic damages were investigated, and technetium-99m-labeled albumin scintigraphy was performed. The serum prostanoid levels were also measured.
Results. In the FK group, pulmonary gas exchange and hemodynamics were significantly (p < 0.05) better, histologic damage and neutrophil infiltration was reduced, and technetium-99m-albumin accumulation was considerably suppressed. Also, thromboxane B2 was significantly (p < 0.05) lower, but 6-keto-prostaglandin F1
was not significantly reduced.
Conclusions. FK3311 generates protective effects on lung transplantation by a marked inhibition of thromboxane A2.
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Introduction
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Lung transplantation is an acceptable therapeutic approach for patients with end-stage lung disease, and short-term survival rates have recently improved [1]. However, donor lungs are particularly vulnerable to ischemia, and the tolerable ischemic time is reported to be shorter than that of other transplantable solid organs [2]. Ischemia–reperfusion (I/R) injury is a significant factor for morbidity, and may result in deterioration of graft function or primary graft failure [3]. The I/R injury is one of the most frequent causes of death within 90 days of lung transplantation, and the mortality rate is as high as 16% to 25% [4, 5]. The acceptable ischemic time is now believed to be 4 to 6 hours, although amelioration of I/R injury in donor organ harvesting, graft preservation, and recipient reperfusion might prolong this time and could lead to safer lung transplantation [6].
Inflammatory reactions are activated in the process of I/R, and inflammatory cytokines, such as tumor necrosis factor- and interleukin-1ß, and arachidonic acid metabolites, such as thromboxane (Tx) A2, prostaglandin (PG) I2, PGE2, or leukotrienes are released [7]. Conversion of arachidonic acid to Txs and PGs is catalyzed by two isoforms of cyclooxygenase (COX); one is the constitutive form (COX-1), and the other is an inducible form (COX-2) [8].
FK3311 (FK; 4'-acetyl-2'- (2,4-difluorophenoxy) methanesulfonanilide; Fujisawa Pharmaceutical Co, Ltd, Osaka) is a nonsteroidal antiinflammatory drug and a selective COX-2 inhibitor that does not cause gastrointestinal irritation or renal dysfunction [9]. The aim of this study was to investigate the effects of FK on I/R injury in a canine lung transplantation model.
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Material and methods
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Animals
Adult mongrel dogs weighing 9 to 12 kg were used in this study. The animals received a standard commercial diet and were allowed free access to food and water until 12 hours before operation. All the 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" published by the National Institutes of Health (NIH publication 85-23, revised 1985). This experimental study was performed with the approval of the Animal Care and Experimentation Committee, Gunma University, Showa Campus.
Donor procedure
After administering intramuscular ketamine hydrochloride (10 mg/kg), the animals were anesthetized with intravenous pentobarbital sodium (10 mg/kg) and pancuronium bromide (0.2 mg/kg). They were then intubated and mechanically ventilated at a tidal volume of 20 mL/kg and a rate of 12 breaths/min. Positive end-expiratory pressure was controlled at 5.0 cm H2O, and the inspired O2 fraction was 1.0. Anesthesia was maintained with inhalation of 1% to 2% halothane, and muscular relaxation was obtained with additional pancuronium bromide (0.1 mg/kg). An arterial line was inserted into the right carotid artery to monitor blood pressure and blood gases. The right external jugular vein was used as a venous infusion line. A left thoracotomy was performed at the fifth intercostal space. The aorta, pulmonary artery, and trachea were isolated. Sodium heparin (300 U/kg) was administered systemically. After clamping the main pulmonary artery, a catheter was inserted into the distal side of the artery while ligating the right pulmonary artery. The left lung was then flushed with 4°C Euro-Collins solution (Kobayashi Pharmaceutical Industry Co, Ltd, Tokyo, Japan) (50 mL/kg) at a perfusion pressure of approximately 40 cm H2O. Simultaneously, the lung was cooled topically by immersing it in saline ice slush. During flushing, the lungs were ventilated continuously. Before flushing the lung, donor lungs were not pretreated with prostaglandins (PGE2 or PGI2), which are now routinely used in clinical lung transplantation. After finishing the flush, the heart–lung block was excised and preserved in 4°C Euro-Collins solution for 12 hours. During preservation, the lungs were kept inflated at an airway pressure of 25 cm H2O. After preservation for 12 hours, the left lung was dissected from the heart–lung block in a basin containing cold Euro-Collins solution.
Recipient procedure
Recipient dogs were anesthetized and ventilated, and catheters were inserted in the same manner as in the donors. After thoracotomy, a left pneumonectomy was performed. Then the donor lung was orthotopically transplanted in the following way. The left atrial anastomosis was performed with running 5-0 Prolene (Ethicon Inc, Somerville, NJ) everting sutures. The arterial and bronchial anastomoses were performed with running 6-0 and 4-0 Prolene sutures, respectively. After completion of these anastomoses, the lung was ventilated and reperfused. At 15 minutes after reperfusion, the right pulmonary artery and main bronchus were ligated; the tidal volume decreased to 10 mL/kg and the respiratory rate increased to 20 breaths/min simultaneously. The chest was then closed, with a drainage tube inserted into the chest cavity. The animals were placed in the supine position and observed for 4 hours of reperfusion.
Experimental design
Twelve pairs of animals were randomly allocated into two groups. In the FK group (n = 6), FK (1 mg/kg) was administered to the donor 15 minutes before ischemia and to the recipient 15 minutes before reperfusion. In the control group (n = 6), vehicle (saline solution) was injected in the same manner as in the FK group.
Hemodynamics and blood gas measurements
During the experiment, arterial blood pressure was monitored continuously. Left pulmonary arterial pressure (L-PAP) was measured by a catheter inserted into the main pulmonary artery and connected to a transducer (Spectramed TA 1017, Sanei Co, Tokyo, Japan). Left atrial pressure (L-AP) was measured through a catheter inserted into the left atrium through the left appendage and connected to a transducer. Cardiac output (CO) was measured by placing an electromagnetic blood flowmeter (MF V-3100, Nihonkohden Co, Tokyo, Japan) on the ascending aorta. Left pulmonary vascular resistance (L-PVR) was calculated using the following formula: 
.
Arterial blood samples were taken to measure arterial oxygen pressure (PaO2) and alveolar–arterial oxygen pressure difference (A-aDO2). The PaO2 was determined by a blood gas analyzer (Stat Profile M, Nova Biomedical Co, Waltham, MA), and A-aDO2 was calculated using the following formulas:
where PiO2 = inspired oxygen pressure and FiO2 = inspired oxygen fraction. In the donor, L-PAP, L-AP, CO, L-PVR, PaO2 and A-aDO2 were measured with clamping the right pulmonary artery before ischemia. In the recipient, these factors were measured after ligating the right pulmonary artery at 15, 30, 60, and 90 minutes and 2, 3, and 4 hours of reperfusion.
Wet-to-dry lung weight ratio measurements
Lung specimens weighing approximately 100 to 300 mg were excised from the tip of the left lung, and the section was closed by ligation. Lung specimens were harvested for wet-to-dry lung weight ratio (WDR) measurements before ischemia in the donor at 2 and 4 hours after reperfusion in the recipient. Wet weights of the lung specimens were measured, and the specimens were dried at 60°C for 5 days, and then their dry weights were measured. The WDR was calculated using the following formula: 
Histopathologic studies and polymorphonuclear neutrophil counts
Lung specimens were harvested in the same manner as mentioned previously for histopathologic studies or polymorphonuclear neutrophil (PMN) counts. The specimens were fixed in 10% formalin, dehydrated, embedded in paraffin, cut into 3- to 5-µm sections, and mounted. After deparafinizing, the tissues were stained with hematoxylin and eosin for histologic studies or stained with naphthol AS-D chloroacetate esterase for PMN counts.
Positive staining PMNs were identified by morphology and counted in high power fields under x400 magnification. At the same time, the alveoli were also counted and the data were expressed as the PMNs/alveolus ratio. A single pathologist, blind to the details of each specimen, performed PMN counts.
Radiologic studies
Pulmonary microvascular permeability of the graft lung was investigated by technetium-99m (99mTc)-labeled human serum albumin (HSA) scintigraphy. The 99mTc-HSA was injected (37 MBq/kg) intravenously at the onset of reperfusion, and the animals were mechanically ventilated without sucking alveolar and bronchial effusions. Four hours after the injection, the pulmonary vasculature was flushed with lactated Ringer’s solution (100 mL/kg) through a catheter inserted into the main pulmonary artery, and the graft lung was resected along with the heart. Scintillation scans of the lung (with heart) were performed to measure 99mTc-HSA accumulation in the interstitial tissue and alveoli of the graft.
Prostanoid (TxB2 and 6-keto-PGF1) measurements
The serum levels of TxB2 (a stable metabolite of TxA2) and 6-keto-PGF1 (a stable metabolite of PGI2) were measured at 30 minutes after reperfusion. The levels were determined using a commercially available, dextran-coated charcoal method radioimmunoassay.
Statistical analysis
All the values are expressed as ± standard error of the mean. Repeated measures analysis of variance was used to compare the groups. If repeated-measures analysis of variance revealed a significant interaction, the statistical significance between the two groups at each time point was determined using Mann-Whitney U test. The animal survival rate was determined using the Kaplan-Meier method, and the log-rank test was used to determine significance. A p value of less than 0.05 was considered to be statistically significant.
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Results
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All 6 animals in each group survived the entire 4-hour interval of reperfusion. There were no significant differences in the preservation time (cold ischemic time) or operating time (warm ischemic time) between the FK and control groups. There were also no significant differences in the mean arterial blood pressure, L-PAP, L-AP, CO, L-PVR, PaO2, A-aDO2, and WDR of the FK and control groups before ischemia in the donor.
During 4-hour observation, there were no significant differences in the L-PAP between the FK and control groups. The L-PVR was significantly (p < 0.05) lower in the FK group than in the control group beginning 60 minutes after reperfusion (Fig 1A). Cardiac output was significantly (p < 0.05) higher in the FK group than in the control group beginning 30 minutes after reperfusion (Fig 1B). The suppression of L-PVR might be related to sustaining higher cardiac output levels in the FK group, as L-PAP levels were similar in the FK and control groups. The PaO2 was significantly (p < 0.05) higher in the FK group than in the control group beginning 30 minutes after reperfusion (Fig 1C). The A-aDO2 was significantly (p < 0.05) lower in the FK group than in the control group beginning 30 minutes after reperfusion (Fig 1D). However, even the FK group exhibited a huge intrapulmonary shunt, with a PaO2/FiO2 ratio of approximately 150 by 4 hours of reperfusion.
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Fig 1. Pulmonary hemodynamics and gas exchange during 4 hours of reperfusion. (A) Left pulmonary vascular resistance (L-PVR), (B) cardiac output (CO), (C) arterial oxygen pressure (PaO2), and (D) alveolar-arterial oxygen pressure difference (A-aDO2). Data are expressed as the mean ± standard error of the mean. *p < 0.05 versus control group.
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The WDR was significantly (p < 0.05) lower in the FK group than in the control group at 2 and 4 hours after reperfusion (Fig 2).
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Fig 2. Wet-to-dry lung weight ratio (WDR) at preischemia and 2 and 4 hours after reperfusion. Data are expressed as the mean ± standard error of the mean. *p < 0.05 versus control group.
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Histologic edema was apparent in the control group, and progressively worsened between 2 and 4 hours after reperfusion. Severe interstitial and alveolar edema and alveolar damage along with inflammatory cell infiltration were observed at 4 hours after reperfusion in the control group, whereas only mild edema was observed in the FK group (Fig 3). The PMN infiltration gradually increased between 2 and 4 hours after reperfusion in both groups, and PMN infiltration at 2 and 4 hours after reperfusion was significantly (p < 0.05) lower in the FK group than in the control group (Fig 4).
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Fig 3. Histopathologic findings of the graft lung at 4 hours after reperfusion in the FK (A) and in the control group (B). (Hematoxylin and eosin, original magnification x50.)
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Fig 4. Polymorphonuclear neutrophil (PMN) counts at preischemia and 2 and 4 hours after reperfusion. Data are expressed as the mean ± standard error of the mean. *p < 0.05 versus control group.
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In the scintigrams 4 hours after reperfusion, there was an obvious 99mTc-HSA accumulation in the graft left lung in the control group, but the accumulation was not as marked in the FK group (Fig 5).
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Fig 5. Technetium-99m-labeled human serum albumin scintigraphy at 4 hours after reperfusion in the FK group (A) and in the control group (B). Technetium-99m-human serum albumin accumulation in the left lung (with heart) was exposed as bright (white) spot.
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The serum TxB2 levels at 30 minutes after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. On the other hand, there were no significant differences in the serum 6-keto-PGF1 levels between the FK and control groups (Fig 6).
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Comment
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After reperfusion, PaO2, A-aDO2, CO, and L-PVR levels were significantly better in the FK group than in the control group. Pulmonary edema, which was estimated with WDR, histologic studies, and 99mTc-HSA scintigraphy, and PMN infiltration were lesser in the FK group than in the control group. These results indicate that FK generates organic protection against I/R injury in lung transplantation.
Cyclooxygenase is a bifunctional intracellular membrane-bound hemeprotein that catalyzes the oxygenation of arachidonic acid to PGG2 and the reduction of PGG2 to PGH2. In turn, PGH2 is converted to several metabolites, including TxA2, PGI2, PGE2, and PGD2 by different prostanoid synthetases [10]. It is often emphasized that COX metabolites have several potent biological activities, which play crucial roles in different conditions. In normal stable conditions, these metabolites are constitutively produced by COX-1, mostly in platelets and endothelial cells, which serve homeostatic functions, such as gastric cytoprotection, maintenance of renal blood flow, and vascular homeostasis [11]. In inflammatory conditions, such as pain, fever, arthritis, trauma, and lipopolysaccharide stimulation, production of these metabolites is temporarily induced by COX-2, mostly in macrophages and monocytes [12]. In the course of pulmonary I/R, arachidonic acid metabolites such as TxA2 and PGI2 are produced along with COX activation.
The TxA2 induces platelet aggregation, stimulates neutrophil aggregation and recruitment, causes vasoconstriction, and increases pulmonary microvascular permeability [13]. In pulmonary I/R injury, vasoconstriction causes microcirculatory disturbance, and platelet and neutrophil aggregation in capillaries further aggravate the disturbance [14]. The PMN sequestration causes tissue damage by adhering to the vasculature, infiltrating local tissues, and releasing superoxides and elastases [15]. In our experiment, we used PMN infiltration as a determination of sequestration. The TxA2 inhibition contributed to the reduction of PMNs in the FK group, and this may be correlated with both histologic damage and edema. Contrarily, PGI2 has several biological effects opposite to TxA2. Prostaglandin I2 inhibits platelet aggregation, suppresses neutrophil aggregation and recruitment, and causes vasodilation [16]. It is uncertain whether PGI2 stabilizes microvascular permeability [17]. Prostaglandin I2 aggravates pulmonary edema by directly increasing vascular endothelial permeability or by increasing blood flow in the area where vascular endothelial cells are injured by reactive oxygen species [18]. However, PGI2 is often used in lung transplantation or I/R injury, both clinically and experimentally because of its beneficial effect in improving tissue blood flow [19]. Except for its effects on vascular permeability, PGI2 ameliorates lung injury.
In I/R injury, COX simultaneously produces TxA2 and PGI2, and these prostanoids balance each other [8]. We measured TxB2 and 6-keto-PGF1 30 minutes after reperfusion. The TxB2 levels were reported mostly elevated immediately after or 10 minutes after reperfusion [13, 20]. We measured TxB2 levels at several time points in our preliminary study of the pulmonary warm ischemia model, and we found the highest levels 30 minutes after reperfusion. Thus, we investigated TxB2 30 minutes after reperfusion. In our experiment, a significant increase in TxB2 and 6-keto-PGF1 was observed in the control group. These prostanoids would generate deleterious effects in the control group by stimulating the inflammatory response. On the other hand, significant lung function was maintained in the FK group, and the increase in TxB2 was significantly inhibited (p = 0.029), whereas the increase in 6-keto-PGF1 was not significantly (p = 0.144) inhibited and remained relatively high compared to the control group. Turnage and colleagues [13] reported that the most crucial change in pulmonary prostanoid release after I/R was the generation of TxA2. Inhibition of TxA2 would contribute to preserving better function in the FK group. With respect to COX inhibition, some researchers have reported that nonselective COX inhibitors, such as indomethacin, significantly inhibited both TxA2 and PGI2 activity, but the drug did not sufficiently ameliorate I/R injury [21]. If a PGI2 analogue was added to the COX inhibitor, these drugs reduced the injury [22]. Several reports suggest that keeping the PGI2/TxA2 ratio high is equally important for minimizing injury [20, 23]. These arguments concur with our results for the FK group, in that the predominant inhibition of TxA2 over PGI2 might contribute to ameliorating injury. As for other prostanoids, PGE2 levels were not as elevated as TxA2 and PGI2 levels after reperfusion, and PGE2 levels were not significantly different between the FK and control groups in our preliminary study. We speculate that process of PGE2 production is complicated and is not regulated solely by COX-2 inhibition with FK. Therefore, we did not report the PGE2 data in our experimental model.
In this experimental model, progressive congestive cardiac failure is inevitable. Because the right pulmonary artery was ligated at 15 minutes after reperfusion, the strain on the right ventricle increased and CO was reduced by pulmonary circulatory congestion [14]. A relative reduction of the negative inotropic effect in the FK group might result from indirect beneficial effects to the general condition and systemic circulation related to the amelioration of I/R injury.
The duration of observation period was relatively short in our experiment compared to other experiments. In our experiment, scintigraphy was performed at the end of the observation period (4 hours after reperfusion). When we performed scintigraphy 6 hours after reperfusion in a preliminary study, vascular washed out with lactated Ringer’s solution was not sufficiently achieved, and 99mTc-HSA might inappropriately remain in the vasculature of the peripheral lung field in the control group. To allow for appropriate evaluation using 99mTc-HSA scintigraphy, we set the end-point of the experiment at 4 hours.
FK3311 was administered at a dosage of 1 mg/kg, which was the most effective dosage used for extended liver resection in a canine ischemia model [24]. The COX-2 induction is initiated by ischemia, and an abrupt release of arachidonic acid metabolites occurs after reperfusion [25]. To deliver the drug throughout the lung before each event, we administered the drug before both ischemia and reperfusion.
In clinical lung transplantation, PGE1 or PGI2 is now routinely used to improve the initial flush and the distribution of preservation solution [26]. Because a high potassium and hypothermic solution is often used for flushing and preservation, these conditions induce severe vasoconstriction and make the initial flush remarkably inadequate [17, 26]. Our experimental model might not follow the standard method, but the purpose of this study was to investigate the effects of a COX inhibitor. For this purpose, we first needed to compare the precise release of prostanoids and its effects in FK-treated and untreated groups. Therefore, we did not use PGE2 or PGI2 in the experimental groups.
In conclusion, a selective COX-2 inhibitor, FK3311, provided organic protection in our experimental model, and may have clinical application in lung transplantation.
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Acknowledgments
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We express our appreciation to Hidenori Ohtake for his expert technical assistance.
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References
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Related Article
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Invited commentary
- John A. Kern
Ann. Thorac. Surg. 2001 72: 1171-1172.
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Abstract
Introduction
