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J Thorac Cardiovasc Surg 1998;116:90-94
© 1998 Mosby, Inc.

Cardiothoracic Transplantation

Effect of soluble complement receptor type 1 on reperfusion edema and neutrophil migration after lung allotransplantation in swine

Supported by Swiss National Science Foundation grant 32-46004.95 and National Institutes of Health grant 1 R01 HL41281.

Presented at the Eighth Congress of the European Society of Organ Transplantation, Sept. 2-6, 1997, Budapest, Hungary.

Received for publication May 27, 1997. Revisions requested July 7, 1997; revisions received Jan. 27, 1998. Accepted for publication Jan. 28, 1998. Address for reprints: Ralph A. Schmid, MD, Department of Surgery, University Hospital, Rämistr. 100, CH-8091 Zürich, Switzerland.

	Abstract

Top Abstract Introduction Materials and methods Results Comment References

 
Objective: Soluble complement receptor type 1 inhibits complement activation by blocking C3 and C5 convertases of the classical and alternative pathways. We evaluated the effect of soluble complement receptor type 1 on lung allograft reperfusion injury.
Methods: Left lung transplantation was performed in 13 weight-matched pigs (25 to 31 kg) after prolonged preservation (20 hours at 1° C). One hour after reperfusion the recipient contralateral right lung was excluded to assess graft function only. Complement activity and C3a levels were measured after reperfusion and at the end of the assessment. Extravascular lung water index, intrathoracic blood volume, and cardiac output were assessed during a 5-hour observation period. Gas exchange and hemodynamics were monitored. At the end of the 5-hour assessment period, myeloperoxidase assay and bronchoalveolar lavage were performed to assess neutrophil migration, and C5b-9 (membrane attack complex) deposits in the allograft were detected by immunohistochemistry. Two groups were studied. In group II (n = 6) recipient animals were treated with soluble complement receptor type 1 (15 mg/kg) 15 minutes before reperfusion. Group I (n = 7) served as the control group.
Results: Serum complement activity was completely inhibited in group II. In contrast to group I, C5b-9 complexes were not detected in group II allograft tissue samples. C3a was reduced to normal levels in group II (p = 0.00005). Extravascular lung water index was higher in group I animals throughout the assessment period (p = 0.035). No significant difference in allograft myeloperoxidase activity (p = 0.10) and polymorphonuclear leukocyte count of the bronchoalveolar lavage fluid (p = 0.057) was detected.
Conclusion: Inhibition of the complement system by soluble complement receptor type 1 blocks local complement activation in the allograft and reduces posttransplantation reperfusion edema but does not improve hemodynamic parameters.

	Introduction

Top Abstract Introduction Materials and methods Results Comment References

 
The pathophysiology of posttransplantation reperfusion injury is not completely understood, but there is much evidence that activation of the nonspecific immune system contributes substantially to postischemic tissue injury. Mediators of reperfusion injury include neutrophil granulocytes, oxygen-derived free radical species, and the complement system. ¹

Postischemic injury in lung allografts can be reduced by leukocyte depletion, inhibition of neutrophil adhesion molecules, and administration of oxygen-derived free radical scavengers during ischemia and reperfusion. The complement system is thought to be involved directly by activation of complement cleavage products and indirectly by complement-mediated neutrophil activation. ²

In vivo, five proteins inhibit the C3 and C5 convertases of the complement system that activate C3 and C5. One of these proteins, the membrane-bound complement receptor type 1 (CR1), is not widely distributed among different cell types and is expressed only on erythrocytes and leukocytes. ³ Elimination of the transmembrane and cytoplasmatic domains results in a soluble form of CR1. ⁴ The remaining extracellular recombinant soluble domain of the complement receptor type 1 (sCR1) retains the inhibitory function on complement activation by inhibiting C3 and C5 convertases of both the classical and alternative pathways. In vivo studies demonstrate that sCR1 is a potent inhibitor of complement-dependent lung and dermal vascular injury and reduces vascular permeability and neutrophil tissue accumulation. ⁵

sCR1 reduces postischemic reperfusion in the myocardium, ^4,6,7 skeletal muscle, ⁸ and the liver. ⁹ A phase I/II trial in lung transplant recipients is planned in the United States to evaluate the effect of sCR1 on posttransplantation lung graft function (Una Ryan, T-cell Science Inc., Needham, Mass.). In the present study we evaluated the effect of recombinant human sCR1 on reperfusion injury in a large animal model of unilateral lung allotransplantation. The swine model was chosen because human recombinant sCR1 is not effective in other large animals, as for example the dog.

	Materials and methods

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Thirteen weight-matched pairs of outbred pigs (aged 3 to 4 months) served as donors and recipients. Harvest and left lung transplantation were performed by a modification of the standard technique performed in dogs as described previously. ¹⁰

Donor procedure
Lungs were harvested from animals whose lungs were ventilated with 100% oxygen and 5 cm H₂O of positive end-expiratory pressure. Before administration of the flush solution (1.5 L, 4° C, Perfadex, P&U/Biophausia AB, Uppsala, Sweden), 250 µg alprostadil (Prostin VR Pediatric; The Upjohn Company, Kalamazoo, Mich.) was injected directly into the main pulmonary artery to achieve maximal vasodilation. The harvested organs were stored in low-potassium-dextran solution (1° C) for 20 hours before implantation.

Recipient procedure
Implantation was performed using standard technique. One hour after reperfusion, the right main pulmonary artery, the arterial branch to the upper lobe, and the right intermediate bronchus were ligated to assess allograft function. The right upper lobe was excluded from ventilation by advancing the tracheal tube to the carina.

Study groups
In group II (n = 6) sCR1 (generously provided by T-cell Sciences Inc., Needham, Mass.) was given to the recipient 15 minutes before reperfusion at a dose of 15 mg/kg. Group I (n = 7) served as control, and no sCR1 was administered. sCR1 was stored at –70° C in aliquots, underwent one thaw-freeze cycle, and was prepared before use.

All 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" prepared by the National Academy of Science and published by the National Institutes of Health (NIH publication No. 85-23, revised 1985). The protocol was approved by the local animal study committee.

Assessment
During the assessment period anesthesia was maintained with halothane (Fluothane) 1.0% to 1.5%. Systemic arterial, pulmonary arterial, central venous, and left atrial pressures were recorded continuously. Arterial and mixed venous blood was collected for gas analysis every 30 minutes. At the end of the assessment period, 5 hours after reperfusion, the animals were killed. Upper lobe allograft samples were submitted to histologic examination and tissue myeloperoxidase assay.

Measurement of extravascular lung water
We modified the previously used large animal model of lung allograft reperfusion injury by the measurement of extravascular lung water as direct assessment of reperfusion edema. A fiberoptic catheter (System Cold Z-021, Pulsion, Munich, Germany) is advanced via the external carotid artery into the descending aorta. The indicator bolus consists of two components. Indocyanine green serves as intravascular marker and ice cold 5% glucose as a thermal intravascular and extravascular indicator. The bolus is injected via the external jugular vein with a temperature-controlled injector. The dilution curves for dye and temperature are recorded simultaneously in the descending aorta with the thermistor-tipped fiberoptic catheter.

Thoracic intravascular and extravascular fluid volumes are determined on the basis of the measurement of the mean transit times for thermal and dye indicators and of the decay time volumes calculated from the indicator-dilution curves as described previously. ¹¹ The lung water computer (System Cold Z-021, Pulsion, Munich, Germany) determines the mean transit time for the thermal indicator and for the dye indicator and calculates total thermal volume (ITTV), intrathoracic blood volume (ITBV), and extravascular thermal volume (ETV). ¹² The extravascular thermal volume (ETV) is calculated as follows: ETV = ITTV – ITBV. All measurements were made every 30 minutes for the first 3 hours and hourly thereafter in triplicate. The mean value was used for analysis.

Assessment of serum complement activity (CH₅₀)
The inhibitory effect of sCR1 on the swine complement system was confirmed with Meyer's hemolysis method to measure complement activity (CH₅₀) as described previously ¹³ (courtesy of Dr. P. Späth, Zentral laboratorium SRK, Berne, Switzerland).

CH₅₀ in the recipient's serum was detected by the same method at the time of reperfusion and at the end of the assessment period 5 hours after reperfusion.

Membrane attack complex (C5b-9, MAC)
Levels of membrane attack complex (MAC) were determined in the pulmonary venous blood by enzyme-linked immunosorbent assay. Zymosan-activated human serum was used as standard defining arbitrary units (AU/ml). MAC deposition in the pulmonary allograft was detected by immunohistochemistry with the use of the same mouse anti-human C9-antibody (C9-neoepitope, clone aE11) that is cross-reactive in pigs. ¹⁴ Tissue samples were taken at the end of the 5-hour assessment period.

Myeloperoxidase assay
Lung samples were frozen immediately and stored at –70° C until assay. Quantitative myeloperoxidase activity was determined as previously described. ¹⁰

Statistical analysis
All values are given as the mean ± standard error of the mean and, where appropriate, the 95% confidence interval of the mean (95% CI) is added. Donor weight, recipient weight, preservation time, warm ischemic time, CH₅₀ activity, C5b-9 activity, C3a levels, neutrophil count in bronchoalveolar lavage fluid, and myeloperoxidase assay were checked for normal distribution within groups and analyzed by the unpaired t test. Gas exchange, hemodynamic parameters, and extravascular lung water were assessed by repeated-measures analysis of variance and planned comparison was applied. For analysis the Statistica 5.1 Software by StatSoft, Inc., Tulsa, Oklahoma (1997), was used.

	Results

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Characteristics of experimental groups
No statistical differences between groups were noted in donor weight (25.6 ± 1.5 kg in group I vs 26.9 ± 1.3 kg in group II, p = 0.54), recipient weight (25.6 ± 2.1 kg in group I vs 26.5 ± 1.2 kg in group II, p = 0.73), preservation time (1209 ± 7 minutes in group I vs 1195 ± 4 minutes in group II, p = 0.13), and warm ischemic time (81 ± 4 minutes in group I vs 89 ± 4 minutes in group II, p = 0.23).

Mortality
Two animals were excluded from analysis. One animal in group I died of mechanically induced ventricular fibrillation after occlusion of the native right pulmonary artery. The second animal (group II) had fever (temperature > 40° C) and severe leukocytosis (>45 x 10³/ml) during the assessment period. For analysis the control group (n = 6) was compared with the sCR1-treated group (n = 5).

Serum complement activity
In vitro
Serum complement activity after addition of sCR1 in normal swine serum assessed by CH₅₀ was markedly reduced at a concentration of 15 ng/ml (9 U/ml) and completely inhibited at a concentration of 150 ng/ml (Fig. 1).

View larger version (18K): [in this window] [in a new window]   Fig. 1. Representative example of inhibition of the complement system by sCR1 in normal swine serum at different concentrations. Complement activity (CH50) was strongly reduced at a concentration of 15 ng/ml and completely blocked at concentrations higher than 150 ng/ml.

View larger version (11K): [in this window] [in a new window]   Fig. 2. Complement activity (CH50) in the recipient animals of the control group and the sCR1-treated group after reperfusion of the transplanted lung (0 hr) and at the end of the assessment period (5 hr) (mean ± standard error of the mean).

Immunohistochemistry demonstrated substantial MAC deposition in group I, whereas in sCR1-treated animals no MAC deposits were detected (Fig. 3).

View larger version (175K): [in this window] [in a new window]   Fig. 3. a and b, Dense deposits of MAC (terminal complement complex, C5b-9) were detected by immunohistochemistry in allograft tissue samples 5 hours after reperfusion. c and d, In sCR1-treated animals no deposits of MAC were detected in the allograft tissue (original magnification x 320).

View larger version (15K): [in this window] [in a new window]   Fig. 4. C3a levels in the pulmonary venous blood in the recipients were tremendously increased in the control group 1 hour and 4 hours after reperfusion of the transplanted lung. sCR1 treatment completely blocked activation of the complement system after lung allograft reperfusion. Normal range of C3a in swine is 181(50 ng/ml (mean ± standard error of the mean).

Hemodynamics
No significant overall group difference was noted in cardiac output (p = 0.28), intrathoracic blood volume (p = 0.54), and pulmonary vascular resistance (p = 0.18) during the 4-hour assessment period (Figs. 5 and 6).

View larger version (22K): [in this window] [in a new window]   Fig. 5. Cardiac output in both groups decreased after occlusion of the right native lung 60 minutes after reperfusion. There is no statistical difference between groups (mean ± standard error of the mean).

View larger version (19K): [in this window] [in a new window]   Fig. 6. Pulmonary vascular resistance (PVR) increased at the time of exclusion of the right native lung. sCR1 treatment did not ameliorate this increase in pulmonary vascular resistance (mean ± standard error of the mean).

View larger version (19K): [in this window] [in a new window]   Fig. 7. Extravascular lung water index (EVLWI) in the pulmonary allograft increased during the first 150 minutes after occlusion of the right native lung (60 minutes), followed by a slight decrease over the next 150 minutes in both groups. Extravascular lung water index was significantly higher in the control group than in the sCR1-treated group (p = 0.035) (mean ± standard error of the mean).

View larger version (27K): [in this window] [in a new window]   Fig. 8. In sCR1-treated recipients, a tendency toward reduced neutrophil (PMN) migration to the allograft was noted in both, neutrophil count in the bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in the allograft upper lobe tissue at the end of the assessment period (mean ± standard error of the mean).

	Comment

Top Abstract Introduction Materials and methods Results Comment References

 
The complement system is part of the humoral first line of defense and a primary mediator of the inflammatory process. Activation of the complement cascade results in interactions between its various components, leading to the generation of products that mediate important immunologic processes. These include promotion of leukocyte activation and chemotaxis through receptor-mediated mechanisms ² and the release of proinflammatory intermediate products of the complement cascade (e.g., C3 and C5). The end product of the complement system is a macromolecular complex, the membrane attack complex (MAC, C5b-C9), which is able to form a channel through the plasma membrane and cause target cell lysis.

The complement system is activated by two separate pathways. The classical pathway is activated by immune complex formation and therefore inactive until the body is challenged with antigen to which it was previously exposed. This condition does not generally occur in allograft recipients. The alternative pathway is activated by nucleophilic chemical structures on the target surface. C3 is cleaved continuously at a slow rate, forming C3b that binds on target surfaces. This process is modulated by regulators of complement activation. If the balance is shifted toward activation by C3b deposition onto a target surface, an explosive positive feedback loop is established, thereby overwhelming the endogenous inhibitors of complement activation. ²

The exact mechanism of complement activation during lung allograft reperfusion remains unknown. It has been shown that oxygen-derived free radicals convert C5 into an active C5b-like form and that neutrophil-derived hydrogen peroxide activates the complement system. Metabolically active cells maintain defense mechanisms that protect them against complement attack. Ischemia and reperfusion could impair their defense by damaging membrane proteins. ¹⁵

Complement cleavage products have a vast number of effects that potentially mediate ischemia-reperfusion injury. C3a and C5a are extremely potent proinflammatory mediators. C5a is 10-fold to 100-fold more active than C3a, but C3 is present in 20-fold greater concentration in the plasma. C3a and C5a induce vasoconstriction, increase vascular permeability, and stimulate granulocyte degranulation. ¹⁶ Furthermore, C5a induces neutrophil adhesion (expression of CD11b/CD18, shedding of L-selectin), ¹⁷ activates endothelial cells, and induces the production of cytokines. C3b and iC3b, its enzymatically inactivated breakdown product, serve as accessory adhesion molecules and bind to CD11b/CD18.

Nonlytic amounts of C5b-C9 (MAC) increase permeability of the target cell membrane, release calcium from intracellular stores, and initiate signaling cascades. This results in activation of a variety of cell functions, including the release of reactive oxygen-derived radicals, production of prostaglandins and leukotrienes, ¹⁸ and secretion of cytokines. Therefore complement activates a wide range of cells without requiring specific receptors. ¹⁹ In endothelial cells, Ca²⁺-dependentactivation by C5b-9 induces P-selectin release from Weibel-Palade bodies to the endothelial membrane. ²⁰

In vivo, sCR1 effectively suppresses complement activation in low doses and reduces inflammatory tissue damage in models of myocardial infarction associated with reperfusion injury. ^4,21 After lower torso ischemia-reperfusion, sCR1 reduces lung injury induced by interleukin-2, endotoxin (accelerated by platelet-activating factor), and pulmonary albumin leak. ^22-24

In piglets undergoing cardiopulmonary bypass for 2 hours, the increase in pulmonary vascular resistance to 338% of baseline in controls was reduced to 147% of baseline in sCR1-treated animals. Gas exchange and leukocyte sequestration were not affected in this model. ²⁵ However, cardiopulmonary bypass in complement-deficient dogs resulted in reduced neutrophil activation, as assessed by CD18 expression. ²⁶

For the present study, development of reperfusion edema was assessed by a lung water computer that determines extravascular thermal volume as a very reliable measurement of extravascular lung water. In vivo data confirm that extravascular thermal volume correlates excellently with postmortem extravascular lung water ²⁷ and morphologic classification of lung edema. ²⁸ However, clinical data revealed only a weak correlation between extravascular thermal volume and the clinical indices of pulmonary dysfunction oxygenation and chest radiography. ^29,30 It seems therefore that extravascular thermal volume is more closely related to the severity of the pathologic status of the lung than is gas exchange, which is used in most reperfusion studies as measurement for reperfusion injury.

We demonstrated that the complement system is activated locally with highly increased deposition of the terminal complement complex (MAC) in the allograft tissue. In sCR1-treated animals no MAC deposits were detected and therefore both the classical and the alternative pathways of complement activation were inhibited by sCR1.

The inhibition of the complement system during reperfusion of lung allografts reduced reperfusion edema in this system but did not improve hemodynamic parameters and pulmonary vascular resistance. In sCR1-treated animals a tendency toward a reduced neutrophil migration into the graft was detected. This may indicate that inhibition of the complement system reduces neutrophil activation during reperfusion. In addition, sCR1-treated recipients demonstrated a tendency toward a better gas exchange of the lung grafts 5 hours after reperfusion, and no deaths resulting from cardiopulmonary failure were observed in this group. In contrast, in the control group, two animals had severe reperfusion edema with rapid deterioration of gas exchange.

Even though only a limited effect on graft function can be expected by an intervention targeted at a single mechanism of the nonspecific immune system, we were able to demonstrate that sCR1 reduces lung allograft reperfusion edema and blocks local complement activation in the allograft. In combination with inhibition of other arms of the inflammatory response, the administration of sCR1 before lung allograft reperfusion may be important to prevent early graft failure.

	References

Top Abstract Introduction Materials and methods Results Comment References

 

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