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Ann Thorac Surg 1999;68:2141-2146
© 1999 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Protective effects of ONO-5046·Na, a specific neutrophil elastase inhibitor, on postperfusion lung injury

^a Department of Thoracic Surgery, Nagoya University School of Medicine, Nagoya, Japan

Address reprint requests to Dr Yamazaki, 65 Tsurumai, Showa-ku, Nagoya 466-0065, Japan

	Abstract

Top Abstract Introduction Material and methods Results Comment References

 
Background. Polymorphonuclear neutrophil elastase might contribute to postperfusion lung injury, so we evaluated the protective effect of ONO-5046·Na, a specific inhibitor of polymorphonuclear neutrophil elastase, against such an injury.

Methods. The study was done using 8 mongrel dogs that received ONO-5046·Na (15 mg/kg per hour) (group O) and 8 control dogs (group C), all of which had 1 hour of partial bypass and 5 hours of observation.

Results. The respiratory index showed no significant changes in group O, but increased significant in group C (1.4 ± 2.0 versus 5.1 ± 4.7, p = 0.0047). Pulmonary extravascular water volume increased markedly in group C but only slightly in group O (group C 20.6 ± 8.7, group O 11.2 ± 2.7 mL/kg; p = 0.0005). Blood concentrations of polymorphonuclear neutrophil elastase and interleukin-6 showed more than a tenfold increase in group C (PMN elastase, group C 12.9 ± 12.8, group O 2.4 ± 1.3 ng/mL; IL-b, group C 11.0 ± 9.3, group O 2.9 ± 3.8 pg/mL; p < 0.05) but were only slightly higher in group O. Histologic examination revealed interstitial and intraalveolar edema in group C, but group O was virtually normal.

Conclusions. ONO-5046·Na inhibits polymorphonuclear neutrophil elastase and maintains better pulmonary function, so it should reduce postperfusion lung injury.

	Introduction

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Pulmonary dysfunction after cardiopulmonary bypass (CPB) is called postperfusion lung syndrome and remains one of the major complications of CPB. Although its mechanism has not been elucidated, activated neutrophils have an important effect on postperfusion lung syndrome. During CPB, blood is exposed to the artificial surfaces of extracorporeal circuits, resulting in the activation of coagulation, fibrinolysis, and platelets. Neutrophils and complement systems are also activated after activation of the contact phase of coagulation. Neutrophil activation originates as a self-defense mechanism, but excessive activation induces tissue injury and causes organ dysfunction. Reperfusion injury after an interruption of pulmonary artery blood flow is another major cause of postperfusion lung syndrome. However, CPB induces neutrophil activation by itself. Activated neutrophils accumulate on the lung and release chemical mediators such as polymorphonuclear neutrophil (PMN) elastase. This mechanism is also important in postperfusion lung syndrome.

Sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046 · Na) (ONO Pharma Co Ltd, Osaka, Japan) is a novel synthesized drug which is a specific inhibitor of PMN elastase. It reduces tissue injury induced by chemical mediators and might protect against pulmonary dysfunction. We performed an experimental study on dogs to evaluate the protective effect of ONO-5046 · Na for CPB-induced pulmonary dysfunction.

	Material and methods

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All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research, the "Guide for the Care and Use of Laboratory Animals," prepared 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 no. 86-23, revised 1985).

Animal preparation and experimental protocol
Sixteen mongrel dogs weighing 17.0 ± 1.5 kg (15.0 to 20.0 kg) were used in this study. Eight were given ONO-5046 · Na continuously (group O), and 8 served as controls (group C). The drug (2,000 mg) was dissolved in 50 mL of 5% glucose solution and administered intravenously at a rate of 15 mg/kg per hour after the initiation of anesthesia until the end of the study. Anesthesia was induced with ketamine hydrochloride (10 mg/kg) given intramuscularly and thiopental sodium (5 mg/kg) given intravenously. After endotracheal intubation, each animal was mechanically ventilated with 100% oxygen. The ventilator rate and tidal volume were adjusted to maintain arterial carbon dioxide tension at approximately 35 mm Hg. Anesthesia was maintained with halothane inhalation and pancuronium bromide (0.1 mg/kg). Catheters were placed in the femoral artery and vein to monitor blood pressure. A Swan-Ganz catheter (model 744H-7.5F; Baxter Healthcare Corporation, Irvine, CA) was inserted in the right external jugular vein to monitor pulmonary artery pressure and to measure cardiac output. A lung-water catheter (HE-2900; Elecath, Tokyo, Japan) was inserted in the femoral artery to measure pulmonary extravascular water volume by the thermal conductivity double indicator-dilution method with a lung water computer (MTV-1100; Nippon Koden, Tokyo, Japan) [1]. A perfusion cannula (12 F) was placed in the femoral artery and a venous cannula in the inferior vena cava via the femoral vein (18 F) and in the superior vena cava via the external jugular vein (18 F) without thoracotomy. Heparin (300 U/kg) was given intravenously before cannulation. Partial CPB was established at a flow rate of 800 mL/minute while oxygenating with pure oxygen at 1.0 L/minute. Hearts were beating and ejecting naturally. Blood temperature was maintained at approximately 37°C with intermittent core heating. Mechanical ventilation was continued, and hemodynamics were maintained properly. The pump circuit consisted of a membranous oxygenator (Menox AL-2000; Kurare, Kurashiki, Japan), a cardiotomy reservoir (3L CARDF PLUS; Shiley, Irvine, CA), and a centrifugal pump (HPM-15; Nikisso, Tokyo, Japan), then primed with 500 mL of electrolyte solution.

Partial CPB was performed for 1 hour and then each dog was weaned from the CPB. Mean blood pressure was maintained at more than 60 mm Hg with appropriate inotropic support and intravenous infusion of electrolyte solution as required. Dogs were kept warm with blankets and cautious observations were made for 5 hours after CPB. Blood gas analysis and blood samplings were done at the initiation and termination of the CPB and in the first, second, third, fourth, and fifth hours after weaning from CPB. After measurement of the data at hour 5, the animal was sacrificed and the left lower lobes of the lung were obtained for histologic study via left thoracotomy. The lung sample was fixed in 10% formaldehyde solution.

Analysis
Blood pressure was measured using a blood pressure monitor (HP7835, Hewlett Packard, Seattle, WA) with disposable transducers (SCK7178; Viggo Spectramed Co, Singapore). The zero pressure level was set at the level of the operating table. Arterial pressure, central venous pressure, pulmonary artery pressure, and pulmonary capillary wedge pressure were recorded at every sampling point. The blood samples were drawn into heparinized syringes and analyzed immediately at 37°C for pH, partial pressure of oxygen, partial pressure of carbon dioxide, oxygen saturation, oxygen content (CaO₂), total carbon dioxide (tCO₂) and hemoglobin (ABL-300; Radiometer, Copenhagen, Denmark). Pulmonary extravascular water volume was measured at every sampling time by a lung-water machine (MTV-1100; Nippon Kohden, Tokyo, Japan). Hemocytograms were also obtained. Plasma was separated from the heparinized blood samples by centrifugation at 1000 g for 10 minutes within 30 minutes of collection, then stored at -80°C until analysis. Duplicate measurements were performed on each sample. PMN elastase (PMN Elastase kit; Merck Immunoassay, Darmstadt, Germany), interleukin-6 (IL-6) (Quantikine human IL-6 Immunoassay; R&D Systems, Minneapolis, MN), and IL-8 (Human IL-8 ELISA system; Amersham Life Science, Buckinghamshire, England) were measured by enzyme-linked immunosorbent assay. Histologic examination was performed on hematoxylin and eosin stained samples by optical microscopy. Neutrophil accumulation on the lung was counted using a 400x magnifier and was expressed as the number of neutrophils on 10 visual fields.

Calculations
Pulmonary vascular resistance (R) was calculated using the formula R = 79,920 x (P_i - P_o)/Q (dynes · sec · cm^-5), where P_i is the mean pulmonary arterial pressure, P_o is the pulmonary capillary wedge pressure, and Q is the cardiac output (mL/minute). Alveolar-arterial oxygen difference (AaDO₂) was calculated with the equation: AaDO₂ = (713 - 5/4 x PaCO₂) - PaO₂. Respiratory index (RI) was calculated from the equation RI = AaDO₂/PaO₂.

Results are expressed as the mean ± standard deviation in the text and the mean ± standard error of the mean in the figures. Statistical significance was determined using the nonpaired t-test and repeated analysis of variance. A p value of less than 0.05 was considered significant.

	Results

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Oxygen transfer capacity
The ratio of partial pressure of arterial oxygen to fraction of inspired oxygen decreased significantly in group C, but it did not change in group O. Group O showed significantly higher values of the ratio than did group C (p = 0.0474) (Fig 1). AaDO2 showed no significant change during the study period in either group, and there were no significant differences in AaDO2 between groups. The respiratory index increased significantly in group C but did not change in group O, remaining less than 1.5. Group O had a significantly lower respiratory index during the study period (p = 0.0047) (Fig 2).

View larger version (24K): [in this window] [in a new window]   Fig 1. Mean values of the ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) of the ONO-5046·Na group (open circles) and control group (open squares). Closed circles and closed squares represent that ratio individually in each dog of the ONO-5046·Na group and control group, respectively, at the beginning and end of study. The X axis indicates time since termination of cardiopulmonary bypass (CPB). An asterisk indicates significant differences (p < 0.05) between groups by nonpaired t test at each point. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

View larger version (21K): [in this window] [in a new window]   Fig 2. Open circles and open squares indicate the respiratory index of the ONO-5046·Na group and control group, respectively. Closed circles and closed squares represent the respiratory index individually in each dog of the ONO-5046·Na group and control group, respectively, at the beginning and end of study. The X axis indicates time since the termination of cardiopulmonary bypass (CPB). An asterisk indicates significant differences (p < 0.05) between groups at each point by nonpaired t test. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

Pulmonary artery vascular resistance
Pulmonary artery vascular resistance decreased after CPB termination and increased gradually 3 hours after CPB termination in both groups. However, there were no significant differences in its value between groups (group C, 386 ± 263 versus group O, 423 ± 214 dynes · sec · cm^-5 at the fifth hour after CPB termination).

Pulmonary extravascular water volume
Pulmonary extravascular water volume increased markedly in group C (p < 0.0001) but only slightly in group O (p = 0.0331). Group C showed twice the pulmonary extravascular water volume as group O after CPB termination, with a statistically significant difference (p = 0.0005) (Fig 3).

View larger version (24K): [in this window] [in a new window]   Fig 3. Pulmonary extravascular water volume of the ONO-5046· Na group (open circles) and control group (open squares). Closed circles and closed squares represent pulmonary extravascular water volume individually in each dog of the ONO-5046·Na group and control group, respectively, at the beginning and end of study. The X axis indicates time since the termination of cardiopulmonary bypass (CPB). Single asterisks and double asterisks indicate significant differences (p < 0.05 and p < 0.01, respectively) between groups at each point by nonpaired t test. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

Blood concentrations of PMN elastase showed a dramatic tenfold increase just after CPB initiation and decreased gradually after CPB termination in group C. On the other hand, group O had less than a fourfold increase in blood concentrations of PMN elastase during and after CPB. There were significant differences in PMN elastase levels between groups (p < 0.0001) (Fig 4).

View larger version (26K): [in this window] [in a new window]   Fig 4. Blood concentrations of polymorphonuclear neutrophil (PMN) elastase. Open circles and open squares represent blood concentrations of PMN elastase of the ONO-5046·Na group and control group, respectively. The X axis indicates time since the termination of cardiopulmonary bypass (CPB). An asterisk indicates significant differences (p < 0.05) between groups at each point by nonpaired t test. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

View larger version (23K): [in this window] [in a new window]   Fig 5. Blood concentrations of interleukin-6 (IL-6). Open circles and open squares represent blood concentrations of IL-6 of the ONO-5046·Na group and control group, respectively. The X axis indicates time since the termination of cardiopulmonary bypass (CPB). An asterisk indicates significant differences (p < 0.05) between groups at each point by nonpaired t test. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

View larger version (25K): [in this window] [in a new window]   Fig 6. Blood concentrations of interleukin-8 (IL-8). Open circles and open squares represent blood concentrations of IL-8 of the ONO-5046 · Na group and control group, respectively. The X axis indicates time since the termination of cardiopulmonary bypass (CPB). An asterisk indicates significant differences (p < 0.05) between groups at each point by nonpaired t test. The p value shows probability of difference between groups by repeated analysis of variance. Error bars show the standard error of the mean.

View larger version (115K): [in this window] [in a new window]   Fig 7. Histologic examination of the lung shows interstitial and intra-alveolar edema and plasma exudation in the alveolar in the control group (A) but virtually normal lung architecture in ONO-5046 · Na group (B). (Hematoxylin and eosin; original magnifications x 100.)

	Comment

Top Abstract Introduction Material and methods Results Comment References

Among the proteases produced by neutrophils, PMN elastase is the most injurious because it is capable of hydrolyzing most connective tissue components on various substrates [9]. It has been reported to have a major influence on lung injury in adult respiratory distress syndrome [10, 11] and to be inhibited by powerful antiproteases such as alpha-1-protease inhibitor or alpha-2-macroglobulin in blood or interstitial fluid in the ordinary state. However, PMN elastase inhibitors are inactivated by superoxide radicals in the microenvironment during an acute inflammatory process. ONO-5046 · Na is a novel, synthesized, specific inhibitor of PMN elastase to the human, rat, mouse, and dog. It works independent of the alpha-1-protease inhibitor and is not inactivated by superoxide radicals [12]. Its molecular weight of 529 D is small enough to achieve close contacts in the microenvironment between neutrophils and substrate, even where alpha-1-protease inhibitor does not reach. ONO-5046·Na moves into tissues more easily and washes out earlier than any other recombinant neutrophil inhibitor [13]. It has been reported that ONO-5046 · Na prevents increases in endothelial permeability induced by PMN elastase and exerts protective effects against pulmonary dysfunction induced by endotoxin or leukotriene B4 [14–16]. ONO-5046·Na shows a dose-dependent inhibition of PMN elastase activity [15]. The proper therapeutic dose of ONO-5046·Na has not been determined; however, at 10 mg/kg per hour, it blocked most lung dysfunction and histopathologic changes of the lung induced by endotoxin in sheep [16]. In dogs, at 10 and 30 mg/kg per hour, ONO-5046·Na reduced 35% to 41% and 64% to 73%, respectively, of PMN elastase activity induced by opsonized zymosan (personal communication from ONO Pharma Co, Ltd, [Osaka, Japan]). The dog shows a better K_i ratio of ONO-5046·Na than human, rat, or mouse. The infusion ratio of this drug at 15 mg/kg per hour in the present study should reveal its efficacy. Actually a dose of 0.004 mg/kg per hour is equal to that of 300,000 IU/day of urinastatine [17]. The toxicity and side effects of ONO-5046·Na are also important in clinical use. A study by the manufacturer found no obvious side effects in a long-term toxicity test in dogs given ONO-5046·Na intravenously at 30 mg/kg per hour for 4 weeks. Tamakuma and associates [17] conducted a phase III clinical study of ONO-5046·Na in 230 systemic inflammatory response syndrome (SIRS) patients. In the overall safety rating, 83% of patients were assessed as safe, and the incidence of adverse drug reactions was 18% at doses of 0.20 mg/kg per hour for 14 days. There were abnormal results of liver function tests, however, that might have been related to SIRS itself. The incidence of side effects probably related with the drug was reported to be only 2% [17].

During CPB, the activation of complement and neutrophils is induced by a blood-foreign body surface reaction. Activated neutrophils increase the affinity of adhesives to activated endothelium through expressed adhesion molecules, and they accumulate in tissue to produce superoxide radicals and chemical mediators such as PMN elastase. In the lung, pulmonary edema originates from an increase in endothelial permeability mainly from PMN elastase, and alveolar hemorrhage is observed as destroying its matrix. In this study, the control group had significant increases in pulmonary extravascular water volume, interstitial and intraalveolar edema, and plasma exudation in the alveoli. Pulmonary dysfunction occurred after CPB revealed a respiratory index over 4.0 (a normal index is less than 1.5). In contrast, the ONO-5046·Na group showed only a slight increase in pulmonary extravascular water volume and no evidence of pulmonary edema by histologic examination. The respiratory index did not change significantly after CPB. These results indicate that ONO-5046·Na inhibits pulmonary edema and pulmonary dysfunction induced by CPB. Because PMN elastase injures the endothelium and produces endothelin, pulmonary vascular resistance might increase. However, ONO-5046·Na showed no improvement in pulmonary vascular resistance in this study. The present study was only 5 hours long, so deterioration of pulmonary architecture might not affect pulmonary circulation until later because pulmonary vascular resistance gradually increased after weaning from CPB in both groups.

In the present study, inflammatory cytokines such as IL-6 and IL-8 were significantly inhibited by ONO-5046 · Na. Although it is not known whether this agent inhibits IL-6 or IL-8 directly, the inhibition of inflammatory reactions by PMN elastase could inactivate the inflammatory cytokine network indirectly. In a clinical study, a close relationship between blood concentrations of PMN elastase and IL-6 or IL-8 after cardiac operations was reported [18]. The IL-6, IL-8, and PMN elastase levels were significantly higher in patients with pulmonary distress after cardiac operations [19]. Therefore, the inhibition of PMN elastase or chemical mediators such as IL-6 or IL-8 should prevent pulmonary edema and pulmonary dysfunction after cardiac operations. We previously reported that CPB circuits made of biocompatible materials, such as heparin coating or another serine protease inhibitor, nafamostat mesilate (FUT-175), reduced blood concentrations of PMN elastase induced by CPB [20]. However, these inhibitory effects on PMN elastase are not essential. ONO-5046 · Na is the strongest PMN elastase inhibitor and should prevent CPB-induced pulmonary dysfunction.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Akihiko Usui Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yamazaki, T. Articles by Yasuura, K. Search for Related Content PubMed PubMed Citation Articles by Yamazaki, T. Articles by Yasuura, K.