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Ann Thorac Surg 1999;67:1428-1433
© 1999 The Society of Thoracic Surgeons
a Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA
Address reprint requests to Dr Kron, Division of Thoracic and Cardiovascular Surgery, Department of Surgery, University of Virginia Health Sciences Center, Box 3111, MR4 Building, Charlottesville, VA 22908
e-mail: ikron{at}virginia.edu
Presented at the Forty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 12–14, 1998.
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Abstract |
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 Top Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Methods. Using an isolated, whole blood-perfused, ventilated rabbit lung model, we sought to characterize the pattern of reperfusion injury and investigate the contribution of neutrophils to this injury. Donor rabbits underwent lung harvest after pulmonary arterial prostoglandin E1 injection and Euro-Collins preservation solution flush. Group I lungs (n = 8) were immediately reperfused without ischemic storage. Group II lungs (n = 8) were stored for 18 h at 4°C before reperfusion. Group III lungs (n = 10) underwent 18 h of ischemic storage and were reperfused with whole blood that was first passed through a leukocyte-depleting filter. All lungs were reperfused for 2 h.
Results. Arterial oxygenation in group III progressively improved, and was significantly higher than that of group II after 2 h of reperfusion (272.58 ± 58.97 vs 53.58 ± 5.34 mm Hg, p = 0.01). Both pulmonary artery pressure and pulmonary vascular resistance were significantly reduced in group III when compared with group II (27.85 ± 1.45 vs 44.15 ± 4.77 mm Hg, p = 0.002; and 30,867 ± 2,323 vs 52,775 ± 6,386 dynes · sec · cm-5, p = 0.003, respectively). Microvascular permeability in group III lungs was reduced to 73.98 ± 6.15 compared with 117.16 ± 12.78 ng Evans blue dye/g tissue in group II (p = 0.005). Group III myeloperoxidase activity was 56.92 ± 6.31 
OD/g/min compared with 102.84 ±10.41 0d/g/min in group II (p = 0.002).
Conclusions. Leukocyte depletion of the blood reperfusate protects against microvascular permeability and significantly improves pulmonary graft function. The neutrophil plays a major role in amplifying lung injury later during reperfusion, and this lung ischemia reperfusion injury may be reversed through the interruption of the inflammatory cascade and the interference with neutrophil infiltration.
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Polymorphonuclear neutrophils have long been recog-nized as critical components of the inflammatory cascade, but their role in lung reperfusion injury has been a source of controversy. Evidence that neutrophils play an important role in the pathophysiology of lung reperfusion injury has been demonstrated in recent studies using leukocyte depletion and also monoclonal antibodies directed against adhesion molecules on leukocytes and endothelial cells [1, 2, 4–8]. In contrast, some investigators have demonstrated that significant ischemia reperfusion injury can occur without neutrophil participation, and that neutrophils may have no effect at all in some models of lung injury [9, 10]. Due to the variability of the models of lung reperfusion injury, the time points of ischemia and reperfusion investigated, and the parameters used to measure reperfusion injury, controversies still exist regarding the importance of neutrophils in lung ischemia reperfusion injury. This study was designed to characterize the pattern of reperfusion injury in a model of lung transplantation and to investigate the contribution of neutrophils to this injury.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Harvest procedure
New Zealand white rabbits of both sexes (3.0 to 3.5 kg) were randomly assigned to the three experimental groups. Each animal was anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (5 mg/kg). Tracheal intubation was performed through a tracheostomy and mechanical ventilation was instituted (Ventilator RSP 1002; Kent Scientific Corporation, Litchfield, CT) with room air at a respiratory rate of 20 breaths/min. A median sternotomy and a thymectomy were then performed. The superior and inferior vena cavae were loosely encircled with ligatures, and the pericardium was opened. Both the pulmonary artery (PA) and the aorta were dissected free and similarly encircled. A purse-string suture was then placed in the free wall of the right ventricle, and intravenous heparin was administered (500 U/kg). After pulmonary arterial injection of 30 µg of prostaglandin E1, the vena cavae were ligated to begin the period of ischemia. The PA was then cannulated through a right ventriculotomy in the center of the purse-string suture, and the right ventricular and PA ligatures were tied to secure the cannula. After the left ventricle was vented through a left ventriculotomy and the aorta was ligated, 50 mL/kg of cold (4°C) Euro-Collins solution was infused into the PA from a height of 30 cm. Topical cooling was achieved with cold saline solution slush. During the PA flush, the left atrium was cannulated through the left ventriculotomy with an outflow catheter and a catheter to directly transduce left atrial pressures. A purse-string suture was placed to secure these cannulae. After completion of the PA flush, the inflow and outflow cannulae were clamped. The lung-heart block was then excised and the tracheostomy tube was clamped at end-inspiration. The inflated lungs were immersed in cold saline solution and were stored at 4°C. 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 85-23, revised 1985).
Reperfusion procedure
After organ harvest and ischemic storage, the lung-heart block was suspended in a warm, humidified tissue chamber, and ventilation was reestablished with a 95% oxygen and 5% carbon dioxide gas mixture at a respiratory rate of 20 breaths/min. The lung-heart block was then connected via the PA catheter and the outflow catheters to a venous blood reperfusion circuit. New Zealand white rabbits served as fresh venous blood donors. The lungs were reperfused with venous blood from a main reservoir. A second nonrecirculated venous blood reservoir was used to challenge the lungs and determine single-pass oxygenation values during reperfusion. In the experimental group designated to undergo leukocyte-depleted reperfusion, venous blood was passed through a leukocyte-depleting filter (Pall Purecell RCQ, East Hills, NY) before being added to both blood reservoirs of the circuit. The perfusion circuit (Kent Scientific Corporation, Litchfield, CT) was designed to recirculate 150 mL of warmed blood with a roller pump (7521-40; Cole-Parmer Instrument Company, Chicago, IL) at a rate of 60 mL/min.
Continuous recordings of PA pressure (PAP), left atrial pressure, airway flow, and airway pressure were performed by a dynamic data acquisition program (Workbench PC; Strawberry Tree, Inc, Sunnydale, CA) on a personal computer (470A; Compaq Prolinea, Houston, TX). This program automatically calculated and displayed pulmonary vascular resistance (PVR), tidal volume, and dynamic airway compliance. Pulmonary venous blood samples were collected for blood gas analysis (Corning 178 pH/Blood Gas Analyzer; Corning Inc, Corning, NY) at 10, 20, 30, 60, and 120 min after the start of reperfusion. At each sampling interval, inflow from the main reservoir was temporarily interrupted and the circuit was filled with nonrecirculated venous blood from the second inflow reservoir. A 30-mL sample of venous blood was passed through the pulmonary vasculature at each interval to obtain accurate measurements of pulmonary venous oxygen content. Oxygen contact with exposed blood surfaces inside the reservoir containers was minimized by continuous passive infusion of 100% nitrogen.
At the conclusion of the reperfusion period, the lungs were then perfused with a 0.9% saline bovine serum albumin solution containing Evans blue dye (EBD; 600 µg/mL) as described by Dallal and Chang [11]. The vascular space was then washed free of this marker with a fresh 0.9% saline solution in a nonrecirculating manner for 6 min. At the completion of the study, samples of the left lower lobe were weighed and dried for calculation of wet/dry weight ratios. Samples of lung tissue taken from the right lung were flash frozen in liquid nitrogen and stored at -80°C for biochemical assays. In addition, specimens from the right lung were placed in formalin, and sections were then processed for hematoxylin and eosin staining and histologic analysis.
Assessment of microvascular permeability
Evans blue dye assay was performed on frozen lung samples from each subject. Lung tissue was placed in 2 mL of formamide and homogenized. The solution was incubated at 37°C for 20 h and then centrifuged at 15,000g for 10 min. Absorbance at 620 nm was measured by spectrophotometry (Model 4050; LKB Biochrom, Cambridge, England). Lung tissue EBD was reported as nanograms of EBD per gram of tissue (wet weight).
Lung tissue myeloperoxidase
Myeloperoxidase (MPO) assay was performed on lung samples to quantify neutrophil sequestration. Tissue was placed in 5 mL of 0.5% hexadecyltrimethylammonium bromide (HTAB) in 50 mmol/L potassium phosphate solution (pH 7.4) and disrupted by homogenizing at 4°C. The solution was centrifuged at 15,000g for 15 min at 4°C, and the supernatant was discarded. The pellet was resuspended in 2 mL of 0.5% HTAB in 50 mmol/L potassium phosphate solution (pH 6.0) and homogenized. Tissue was disrupted further by sonication and then underwent three freeze-thaw cycles (liquid nitrogen bath/37°C water bath). The solution was then centrifuged at 15,000g for 15 min at 4°C. Aliquots (0.1 mL) of supernatant were added to the assay buffer of O-dianisidine, H2O2, and 50 mmol/L potassium phosphate (pH 6.0). Absorbance at 460 nm was measured over 2 min by spectrophotometry (Model 4050; LKB Biochrom). Lung tissue MPO activity was expressed as change in absorbance/g/min.
Statistical analysis
Statistical analysis was performed for the three groups using analysis of variance (ANOVA) on SPSS software (SPSS Inc, Chicago, IL). In addition, a repeated measures ANOVA was performed for data with multiple time points. Significant differences were determined using Tukey’s honestly significant difference test. Values of p less than or equal to 0.05 were considered statistically significant. The data are expressed as the mean plus or minus the standard error of the mean.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Physiologic parameters
Throughout the 2-h reperfusion period, group III lungs that underwent reperfusion with leukocyte-depleted blood displayed a progressive improvement in arterial oxygenation. The arterial pO2 of group III lungs was significantly higher than the pO2 of group II lungs at 60 min of reperfusion (269.22 ± 44.18 mm Hg vs 57.94 ± 5.10 mm Hg, p = 0.005) and at 120 min of reperfusion (272.58 ± 58.97 mm Hg vs 53.58 ± 5.34 mm Hg, p = 0.01). The arterial pO2 of group I lungs that were immediately reperfused with whole blood was consistently higher than that of the lungs in group II, establishing a reliable injury after 18 h of cold ischemic storage (Fig 1). Mean pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (PAP) were significantly lower in group III lungs as compared with group II lungs at 20, 30, 60, and 120 min of reperfusion (Fig 2). At the conclusion of the 2-h reperfusion period, PVR was 30,867 ± 2,323 dynes · sec · cm-5 in group III and 52,775 ± 6,386 dynes · sec · cm-5 in group II (p = 0.003); PAP was 27.85 ± 1.45 mm Hg in group III and 44.15 ± 4.77 mm Hg in group II (p = 0.002). The dynamic airway compliance was significantly higher in the group I control lungs when compared with the group II control lungs (1.49 ± 0.04 mL/mm Hg vs 1.08 ± 0.12 mL/mm Hg, p = 0.015). Leukocyte depletion of the blood reperfusate in group III increased the airway compliance to 1.31 ± 0.08 mL/mm Hg, but this did not reach statistical significance when compared with group II.
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Microvascular permeability
EBD was used to determine microvascular permeability and to quantitate injury to the lung. In our control groups, the level of lung injury was significantly lower in lungs that were immediately reperfused (group I) than in lungs that underwent 18 h of ischemic storage before reperfusion with whole blood (group II) (89.29 ± 5.07 ng/g tissue vs 117.16 ± 12.78 ng/g tissue, p = 0.005). This ischemia reperfusion lung injury was significantly reduced with leukocyte depletion of the blood reperfusate. The concentration of EBD in group III lungs dropped significantly to 73.98 ± 6.15 ng/g tissue when compared with group II (p = 0.005). (Fig 3).
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OD/g/min in group I, 75.38 ± 8.19 OD/g/min in group II, and 80.00 ± 13.05 OD/g/min in group III (p = 0.874). However, after 2 h of reperfusion, the tissue MPO activity in the group III lungs (56.92 ± 6.31 OD/g/min) was significantly lower than the MPO activity in group II (102.84 ± 10.41 OD/g/min) and in group I (105.21 ± 12.69 OD/g/min) (p = 0.002) (Fig 4). In addition, the control lungs in group II displayed a significant rise in tissue MPO activity between 30 and 120 min of whole blood reperfusion (p = 0.05).
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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, interleukin-1 (IL-1), IL-6, and IL-8, all of which have far-reaching effects on the inflammatory process [1, 4, 5]. The timing of neutrophil involvement in reperfusion injury remains uncertain and continues to be a focus of recent investigations. Breda and colleagues, employing a model of leukocyte depletion, reported that leukocytes were a critical component of lung injury in the first hour of reperfusion and that the role of WBC after the first hour of reperfusion was substantially less [2]. In a rat model of lung ischemia reperfusion injury, Eppinger and colleagues demonstrated a bimodal pattern of injury during reperfusion [4]. The acute phase of injury occurred within the first 30 min of reperfusion, neutrophils had no significant role in this first peak, and the acute injury was partially reversible. After the first hour of reperfusion, however, there was a gradual increase in lung injury that was associated with a progressive increase in neutrophil sequestration, suggesting a neutrophil-dependent pathophysiology of the later peak of injury. Studies of leukocyte kinetics within the pulmonary vasculature showed that the number of sticking leukocytes in pulmonary arterioles, venules, and alveolar capillaries increased significantly within 10 min after reperfusion. In addition, a further significant increase in sticking leukocytes was found after 1 h of reperfusion [17].
In the current study, we demonstrate an important role of circulating leukocytes in the inflammation of lung reperfusion injury. Leukocyte depletion of the blood reperfusate had a significant protective effect against microvascular permeability and improved arterial oxygenation, pulmonary artery pressure, and pulmonary vascular resistance after 18 h of ischemic storage and 2 h of reperfusion. During this time course of reperfusion, we then more clearly defined the contribution of neutrophils to lung injury. We discovered a relationship between neutrophils and lung injury that parallels the findings of Eppinger and colleagues [4]. After only 30 min of reperfusion, there were no significant differences in MPO activity. However, during the time period from 30 to 120 min after reperfusion, there was a significant increase in the MPO activity in the group of control lungs after 18 h of ischemic storage. This rise in tissue neutrophil sequestration was associated with a significant increase in microvascular permeability and lung injury. The leukocyte-depleted group of lungs displayed a substantial decrease in the level of neutrophil sequestration in both the results of MPO activity and histologic analysis after 2 h of reperfusion. The decreased neutrophil activity in this group correlated well with a significantly reduced level of microvascular permeability, as measured by EBD, and a progressive improvement in arterial oxygenation during the period of reperfusion. The steady improvement in the lungs that underwent leukocyte-depleted reperfusion suggests that the reperfusion injury displayed after 18 h of ischemia may be reversed if the subsequent tissue neutrophil infiltration is prevented. Interestingly, the MPO activity in the control lungs that were immediately reperfused with whole blood was also significantly higher than the leukocyte-depleted group, but there was minimal evidence of lung injury. This suggests that the lung injury present after 2 h of reperfusion is dependent on both ischemia and neutrophil infiltration.
A disadvantage of mechanical leukocyte depletion may be concomitant removal of platelets, with consequent promotion of perioperative bleeding. Our study in an isolated organ model is unable to address this question, but other studies do not support this concern [6, 18]. Another experimental concern of thrombocytopenia is the suggestion that platelets may be important components of microvascular aggregates and mediators of ischemia reperfusion injury, and that thrombocytopenia and neutropenia may together be responsible for reduced tissue injury. Some investigators believe that platelets do play an important role in the pathophysiology of ischemia reperfusion injury [13]. Platelets may directly contribute to reperfusion injury by way of increased aggregability and may indirectly influence this injury as their release of thromboxane and other agents may contribute to the upregulation of the inflammatory cascade and to neutrophil activation. However, others have shown that platelets are not directly involved in reperfusion injury. In studies using mechanical leukocyte depletion with cardiopulmonary bypass, platelet counts were not depressed any more than after bypass alone, and yet, lung function parameters were significantly improved with leukocyte depletion [6]. In addition, intravital microscopy and 111In-labeling of platelets have demonstrated that platelets do not accumulate in ischemic tissue during reperfusion, in contrast to the consistent presence of neutrophils [13]. These considerations, though, do not deny the possible indirect role of platelets in promoting the activation of the inflammatory cascade. Our current study does not isolate the influence of platelets on ischemia reperfusion injury but does suggest that thrombocytopenia may play a role in limiting lung reperfusion injury. An additional concern about leukocyte depletion is the potential subsequent development of serious infections. It is unclear as to the length of time that leukocyte counts remain abnormal after filtration, but initial studies do not demonstrate different infection rates [19].
Circulating leukocytes clearly play a major role in the cascade of tissue destruction resulting from reperfusion of the ischemic lung. We believe that the neutrophil is a progressively important contributor to this lung injury over the time course of reperfusion. Pulmonary ischemia reperfusion injury is sufficiently complex that it seems likely that no one cell type is solely responsible for its induction. In fact, endothelial cells, alveolar macrophages, and mast cells have all been implicated as possible destructive forces at the beginning of reperfusion [1]. Many of these cells then secrete neutrophil chemotactic factors that lead to leukostasis and microvascular occlusion in the lung. The local generation and release of toxic oxygen-free radicals and proteolytic enzymes from activated neutrophils promotes further endothelial injury, resulting in vasospasm and an increase in pulmonary vascular resistance. Subsequently, increased microvascular permeability results in increased edema formation and deterioration in oxygenation.
We conclude that the neutrophil plays a major role in amplifying lung injury later during reperfusion after transplantation. This lung ischemia reperfusion injury may be reversed through the interruption of the inflammatory cascade and the interference with neutrophil infiltration. We have demonstrated in an isolated lung model that mechanical leukocyte filtration significantly reduces tissue neutrophil infiltration and provides excellent pulmonary graft function after 18 h of organ ischemia. Our isolated lung model provided a controlled setting for these experiments, but it may cause some injury itself and it does not offer the advantages of a whole-animal model. Clinical correlation is also required for discerning potential disadvantages of leukocyte filtration.
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Acknowledgments |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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TopAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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