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Ann Thorac Surg 2001;71:1134-1139
© 2001 The Society of Thoracic Surgeons

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Original article: general thoracic

Pulmonary macrophages are involved in reperfusion injury after lung transplantation

^a Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, Charlottesville, Virginia, USA

Address reprint requests to Dr Kron, Department of Thoracic and Cardiovascular Surgery, University of Virginia Health Sciences Center, PO Box 801359, Lane Rd, MR4 Building, Room 3111, Charlottesville, VA 22908
e-mail: ikron{at}virginia.edu

Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9–11, 2000.

	Abstract

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Background. Reperfusion injury is a perplexing cause of early graft failure after lung transplantation. Although recipient neutrophils are thought to have a role in the development of reperfusion injury, some researchers have shown that neutrophils are not involved in its earliest phase. Intrinsic donor pulmonary macrophages may be responsible for this early phase of injury. Using the macrophage inhibitor gadolinium chloride, we attempted to investigate the role of pulmonary macrophages in reperfusion injury after lung transplantation.

Methods. Using our isolated, ventilated, blood-perfused rabbit lung model, all groups underwent lung harvest followed by 18-hour storage (4°C) and blood reperfusion for 30 minutes. Group I served as a control. Group II received gadolinium chloride at 7 mg/kg 24 hours before harvest. Group III received gadolinium chloride at 14 mg/kg 24 hours before harvest.

Results. Group III had significantly improved arterial oxygenation and pulmonary artery pressures compared with groups I and II after 30 minutes of reperfusion.

Conclusions. The earliest phase of reperfusion injury after lung transplantation involves donor pulmonary macrophages.

	Introduction

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Considerable advancements in lung transplantation during recent years have led to the use of this life-saving operation for more patients with various end-stage pulmonary diseases. Most of the early advances focused on optimal organ preservation techniques and solutions. Despite these improvements, however, transplanted lungs remain vulnerable to ischemia-reperfusion injury, with severe graft dysfunction occurring in 20% of lung transplant recipients [1, 2]. Although severe graft dysfunction can be reversible, it is often associated with the need for prolonged intensive care and increased mortality [3, 4]. Although ischemia is clearly involved, it has become increasingly evident that reperfusion is responsible for most tissue injury after lung transplantation [5]. In addition, studies have confirmed that the lung injury is a result of upregulation and activation of inflammatory mediators after reperfusion [6, 7].

Although the inflammatory system has a role in reperfusion injury after lung transplantation, the timing and involvement of the exact cellular components is unclear. Polymorphonuclear neutrophils, specifically, have long been recognized as critical components of the inflammatory cascade, but their role in the pathophysiology of lung reperfusion injury has been a source of controversy. Evidence that neutrophils play an important role in lung reperfusion injury has been demonstrated in recent investigations using leukocyte depletion and in studies with antibodies directed against adhesion molecules on leukocytes and endothelial cells [2, 5–10]. In contrast, some investigators have demonstrated that significant reperfusion injury can occur without neutrophil participation and that neutrophils may have no effect at all in the earliest phase of lung reperfusion injury [11, 12]. Recent work with cytokine antibodies suggests that pulmonary macrophages may have a role in the earliest phase of reperfusion injury [7]. Macrophages could potentially initiate reperfusion injury with further escalation induced by circulating leukocytes. Gadolinium chloride (GdCl₃), a rare lanthanide earth salt, inactivates macrophages by suppressing phagocytic and inflammatory responses [13]. This compound has been used in recent studies to inhibit alveolar macrophages [14, 15]. The goal of the present study was to investigate the role of pulmonary macrophages in a lung model of transplant reperfusion injury by using the macrophage inhibitor GdCl₃.

	Material and methods

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Experimental protocol
Three experimental groups were compared in an isolated, blood-perfused, ventilated rabbit lung model of transplantation. Group I lungs (control group, n = 8) were harvested and then stored for 18 hours at 4°C before reperfusion with whole blood. Group II rabbits (low-dose GdCl₃ group, n = 8) were given intravenous GdCl₃ (7 mg/kg, Sigma Corporation, St. Louis, MO) 24 hours before harvest, followed by lung storage for 18 hours at 4°C and reperfusion with whole blood. Group III rabbits (high-dose GdCl₃ group, n = 8) were given intravenous GdCl₃ (14 mg/kg) 24 hours before harvest, followed by lung storage for 18 hours at 4°C and reperfusion with whole blood. Drug doses were determined after a preliminary experiment using doses of GdCl₃ at 1, 7, 14, and 28 mg/kg.

Harvest procedure
Adult New Zealand white rabbits of both sexes weighing 3.0 to 3.5 kg were randomly assigned to the three experimental groups. Animals were anesthetized with intramuscular ketamine (50 mg/kg) and xylazine (5 mg/kg). Tracheal intubation was performed through a tracheostomy and mechanical ventilation was instituted with a constant pressure ventilator (#RSP1002, Kent Scientific Corp, Litchfield, CT) using room air and a rate of 20 breaths/minute. A median sternotomy and thymectomy were then performed. The two superior and one inferior vena cavas were loosely encircled with ligatures and the pericardium was opened. Both the pulmonary artery (PA) and aorta were dissected free and similarly encircled. A purse-string suture was placed in the free wall of the right ventricle and intravenous heparin was administered (500 units/kg).

After injection of 30 µg of prostaglandin E₁ (alprostadil; Upjohn Company, Kalamazoo, MI) into the PA, the cavas were interrupted and onset of ischemia was noted. The PA was then cannulated through a right ventriculotomy placed in the center of the purse-string suture. Both the right ventricle and PA ligatures were tied to secure the cannula. After venting the left ventricle with a left ventriculotomy and ligating the aorta, 50 mL/kg of Euro-Collins (Hamburg, Germany) preservation solution at 4°C 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 cannulas. Following completion of the PA flush, the inflow and outflow cannulas were clamped. The heart-lung block was then excised and the tracheostomy tube was clamped at end-inspiration. The inflated lungs were stored immersed in saline solution at 4°C for 18 hours. 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 1996).

Reperfusion procedure
After organ harvest and ischemic storage, the heart–lung 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/minute using the constant pressure ventilator (Fig 1). The inflow and outflow cannulas were then connected to a venous blood reperfusion circuit. New Zealand white rabbits weighing 3.5 to 5.0 kg 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 the single pass oxygenation values during reperfusion. The circuit (Kent Scientific Corp) was designed to recirculate 150 mL of warmed blood using a roller pump (#7521-40, Cole Palmer Instrument Co, Chicago, IL) at 60 mL/minute.

View larger version (21K): [in this window] [in a new window]   Fig 1. Isolated, blood-perfused rabbit lung model. Diagram of the isolated lung model. (P = pressure transducer, N2 = nitrogen gas, O2 = oxygen gas.)

Lung wet-to-dry weight ratios
Lung wet-to-dry weight ratios were used as a measurement of pulmonary edema. Samples of lung tissue were weighed immediately following reperfusion. These samples then underwent passive desiccation at room temperature until a stable dry weight was achieved. The weight immediately following reperfusion and the stable dry weight were then used to calculate the lung wet-to-dry weight ratios.

Lung tissue myeloperoxidase
A myeloperoxidase (MPO) assay was performed to quantify neutrophil sequestration. Lung tissue was placed in 5 mL of 0.5% hexadecyltrimethyl-ammonium 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 minutes at 4°C and the supernate 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 three freeze-thaw cycles (liquid nitrogen bath/37°C water bath). The solution was again centrifuged at 15,000g for 15 minutes at 4°C. Aliquots (0.1 mL) of supernatant were added to the assay buffer of O-dianisdine dihydrochloride, H₂O₂, and 50 mmol/L potassium phosphate (pH 6.0). Absorbance at 460 nm was measured over 2 minutes by spectrophotometry (LKB Model 4050, Cambridge, England). Protein concentration for each of the lung samples was measured using the BCA protein assay kit from Pierce (Rockford, IL). Protein concentrations were calculated by comparing the absorbance at 595 nm of the experimental samples with that of known bovine serum albumin standard concentrations in the same assay. Lung tissue MPO activity was expressed as change in absorbance/g protein per minute.

Statistical analysis
Statistical analysis was performed using analysis of variance on SPSS software (SPSS Inc, Chicago IL). Significant differences were determined using Tukey’s significant difference test. Values of p less than or equal to 0.05 were considered significant. Data are expressed as the mean ± the standard error of the mean.

	Results

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Arterial pO₂ was significantly higher in the high-dose GdCl₃ (320 ± 13.3 mm Hg, p < 0.001, Fig 2) and low-dose GdCl₃ (78.4 ± 5.9 mm Hg, p < 0.001) groups compared with the control (42.9 ± 2.7 mm Hg) group after 30 minutes of reperfusion. Arterial pO2 was also significantly higher in the high-dose GdCl₃ than in the low-dose GdCl₃ group (p < 0.001). The oxygen content was significantly higher in the high-dose GdCl₃ (3,962 ± 51.6 mm Hg, p < 0.001) and low-dose GdCl₃ (3,302 ± 113.2 mm Hg, p < 0.001) groups compared with the control group (2,914 ± 389.7 mm Hg) after 30 minutes of reperfusion. The high-dose GdCl₃ group also had a significantly improved oxygen content compared with the low-dose GdCl₃ group (p < 0.001). Hemoglobin level was not significantly different between the high-dose GdCl₃ (29.3 ± 0.77 g/dL), low-dose GdCl₃ (28.0 ± 0.79 g/dL), and control groups (29.0 ± 0.38 g/dL).

View larger version (15K): [in this window] [in a new window]   Fig 2. Arterial oxygenation (pO2). The high-dose and low-dose GdCl3 groups had significantly improved pO2 measurements after 10, 20, and 30 minutes of reperfusion compared with the control group. *p < 0.001 versus control.

View larger version (15K): [in this window] [in a new window]   Fig 3. Pulmonary artery pressure (PAP). The control group had a significantly higher PAP compared with the high-dose and low-dose GdCl3 groups after 10, 20, and 30 minutes of reperfusion. *p < 0.001 versus control.

	Comment

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Although many investigations have confirmed the role of neutrophils in reperfusion injury, others have questioned neutrophil involvement. Deeb and colleagues [12] demonstrated that neutrophils are not necessary to induce reperfusion injury in a rat lung preparation using isolated blood cell components. Their study reported attenuation of injury with the addition of red blood cells or catalase. The authors concluded that a non-neutrophil source of oxygen metabolites, such as lung macrophages, were responsible for the observed injury. Steimle and colleagues [11] also demonstrated neutrophil-independent reperfusion injury using neutrophil antibodies in an in vivo rat lung model at 90 minutes of reperfusion. Their study demonstrated no accumulation of neutrophils in the damaged lungs of the non–neutrophil-depleted rats when compared with the injured lungs of the neutrophil-depleted rats based on histologic and electron microscope findings. Eppinger and coworkers [6] performed a similar in vivo study and found that neutrophil depletion had no protective effect after 30 minutes of reperfusion, but did attenuate injury after 4 hours. Our own studies have also confirmed this finding. In experiments involving leukocyte filtration before reperfusion, improvement in lung function occurred gradually and was maximal after 120 minutes of reperfusion. Further, our studies on MPO in control lungs at 30 and 120 minutes demonstrated significantly increased MPO activity after 2 hours of reperfusion compared with 30 minutes [10]. These findings further suggest neutrophil involvement in reperfusion injury occurs during the late phase of reperfusion and that other mechanisms or cells are responsible for the earliest phase of reperfusion injury.

A recent investigation by Eppinger and colleagues [7] strengthens the likelihood that lung macrophages are involved in the early phase of lung reperfusion injury. In their study, the chemical mediators of reperfusion injury in the rat lung were characterized. Tumor necrosis factor-alpha (TNF-), interferon gamma (IFN-), and monocyte chemoattractant protein-1 were shown to be required for early injury by using cytokine-specific antibodies. One possible mechanism for the decreased injury with anti-TNF- and anti-IFN- is through suppression of macrophage function. Both TNF- and IFN- are known to be important factors in the respiratory burst activity and other inflammatory functions of macrophages. They also found that anti-monocyte chemoattractant protein-1, which is an antibody against a highly specific macrophage activator and has no activity on neutrophils, dramatically decreased the early phase of injury. The authors concluded that early lung injury is in large part determined by products of activated macrophages, whereas delayed injury is mediated mostly by products of activated and recruited neutrophils. Using GdCl₃, the current study supports a role for macrophage involvement in reperfusion injury. Gadolinium chloride has been shown in previous experiments to inactivate macrophages by suppressing phagocytic, immune, and inflammatory responses [13–15]. At 30 minutes of reperfusion, macrophage inhibition with GdCl₃ significantly attenuated the poor oxygenation found in control lungs. Similarly, macrophage inhibition resulted in improved PAP and PVR measurements after 30 minutes of reperfusion. There was also a trend toward improved wet-to-dry weight ratio and lung compliance in the high-dose GdCl₃ group compared with the control group after 30 minutes of reperfusion. Had this experiment been performed over a longer period of time, the control group would have likely had a further increase in pulmonary edema, resulting in a statistically significant difference in wet-to-dry ratio and lung compliance compared with the high-dose GdCl₃ group.

Most of the research in the area of lung reperfusion injury has focused on the recipient inflammatory system. However, activation of donor, resident alveolar macrophages could be the initiating factor in lung damage. This model would suggest that macrophages in donor lungs are activated early on by preservation and reperfusion. These cells subsequently release cytokines, chemoattractants, and proteolytic enzymes that induce an early reperfusion injury. This early damage is then followed by a cascade of events leading to activation of the recipient inflammatory system against the already damaged lung tissue [2, 7]. This model of lung ischemia-reperfusion injury helps explain the early, neutrophil-independent, reperfusion injury reported by some groups.

In conclusion, pulmonary ischemia-reperfusion injury is a complex process, likely involving many cell types, cytokines, and mechanisms. Neutrophils have been shown in our previous investigations and in studies by others to be involved in the late phase of reperfusion injury. Macrophage inhibition with GdCl₃, however, significantly attenuates at least the earliest (30 minute) phase of reperfusion injury. Thus, both pulmonary macrophages and circulating neutrophils seem to have roles in lung reperfusion injury after transplantation. Clinical application of GdCl₃, however, is unlikely in the transplant setting because it must be given 24 hours in advance. However, administration of other macrophage inhibitors, such as intratracheal antimacrophage antibodies, may have a potential role in clinical lung transplantation.

	Acknowledgments

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The authors acknowledge Anthony Herring and Sheila Hammond for their technical advice and support. This work was supported by the National Institutes of Health under R01 grant HL56093-03 and National Research Service Award F32 grant HL10248-01.

	Discussion

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DR DARRYL S. WEIMAN (Memphis, TN): Are you recommending that we start to perfuse our lungs with this gadolinium before we transplant these patients with these lungs?

DR FISER: One of the technical aspects of using gadolinium chloride is that in our experience you have to give it 24 hours in advance. The macrophages need to be able to uptake the gadolinium and sort of have that whole process occur. This would not be something you could do two hours before you harvested.

DR WEIMAN: So clinically we have to wait for something like gadolinium to use?

DR FISER: We would need a better way of inhibiting pulmonary macrophages before we could use this clinically.

DR FREDERICK L. GROVER (Denver, CO): Very nice paper. Have you also looked at nitric oxide as an inhibitor of macrophage production?

DR FISER: We have looked at nitric oxide as well as nitric oxide donors, such as nitroprusside, but we have not specifically analyzed that effect on macrophages. I can tell you that we have found improvement in reperfusion injury when we have used nitric oxide donors and nitric oxide, but again the specific impact on pulmonary macrophages is not known.

DR JAKOB VINTEN-JOHANSEN (Atlanta, GA): That was a very nice study. How specific is gadolinium for macrophages? In addition, have you looked at other proteins, et cetera, and signals that trigger macrophages specifically, like MCP-1 (macrophage chemotactic protein-1), to see if it correlates with macrophage appearance, because macrophages tend to be activated later due to MCP upregulation?

DR FISER: That is a very good question. Gadolinium chloride is not a very specific inhibitor of macrophages. It is not direct like using an antibody against macrophages.

I think the one thing that has been underappreciated a little, if you look at the inflammatory cascade and inflammatory response, is that usually neutrophils are involved first, followed by a macrophage response. What I think that is different about lung transplantation is that the lung has a lot of macrophages in it already. The primary job of pulmonary macrophages is to clear debris that is inhaled. So you have this large inflammatory cell population already present in the lung that might be accounting for the early response that we see.

As far as looking at MCP, those and some of the other macrophage proteins that are released, we have not specifically looked at yet, but that is definitely a future course of investigation at our lab.

DR ARA A. VAPORCIYAN (Houston, TX): One blood-borne component that is usually implicated in rapid onset of inflammatory injury is complement. It has been shown by Peter Ward’s lab, which is where Eppinger reported, as well as Dr Deed’s lab, that complement is usually involved in injury that occurs within 30 minutes. Did you look at the effects of gadolinium chloride on complement or the amount of complement left in your whole blood perfusate?

DR FISER: We have not specifically looked at complement.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments Discussion 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): Curtis G. Tribble John A. Kern Irving L. Kron Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fiser, S. M. Articles by Kron, I. L. Search for Related Content PubMed PubMed Citation Articles by Fiser, S. M. Articles by Kron, I. L. Related Collections Lung - transplantation