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J Thorac Cardiovasc Surg 2000;120:1078-1084
© 2000 The American Association for Thoracic Surgery

General Thoracic Surgery

sCR1sLe^X ameliorates ischemia/reperfusion injury in experimental lung transplantation

From the Division of General Thoracic Surgery,^a University Hospital, Berne, Switzerland, the Institute of Biochemical Pharmacology,^b University of Constance, Konstanz, Germany, and the Division of General Thoracic Surgery,^c University Hospital, Zurich, Switzerland.

Supported by a grant from the EMDO-Stiftung.

Address for reprints: R. A. Schmid, MD, Division of Thoracic Surgery, University Hospital, 3010 Berne, Switzerland (E-mail: ralph.schmid{at}insel.ch).

	Abstract

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Background: The nonspecific immune response with activation of the complement system and polymorphonuclear leukocytes is important for the mediation of reperfusion injury after lung transplantation. In this study, we investigated the combined blockade of the complement system and leukocyte adhesion by a novel drug combining soluble complement receptor type 1 (sCR1, CD35) with the selectin ligand sialyl Lewis X (sLe^X, CD15s) synthesized to sCR1sLe^X. Both sCR1 and sCR1sLe^X were supplied by AVANT Immunotherapeutics, Inc, Needham, Massachusetts.
Methods: Orthotopic allogeneic single left lung transplantation was performed in male rats (Brown Norway to Fischer F344; n = 5 in all groups) after a total ischemic time of 20 hours. Recipients received either no specific treatment (control) or administration of sCR1 (10 mg/kg) or sCR1sLe^X (10 mg/kg) 15 minutes before reperfusion by intracardiac injection. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only. In additional animals (5 per group), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity as a measurement of neutrophil migration into the graft and thiobarbituric acid reactive substances to quantify lipid peroxidation.
Results: Graft function as assessed by arterial PO₂ in recipients treated with sCR1sLeX was superior not only to that of controls (383 ± 53 vs 56 ± 7 mm Hg, P = .000095) but also to that of animals treated with sCR1 (243 ± 45 mm Hg, P = .031). This improvement was confirmed by significant reduction of neutrophil migration (0.33 ± 0.05 vs control, 1.0 ± 0.09 OD/mg/min, P = .0000024) and lipid peroxidation (6.2 ± 0.38 vs control, 10.6 ± 0.54 pmol/g, P = .00021).
Conclusions: Our data indicate that combined inhibition of complement activation and leukocyte adhesion with sCR1sLe^X reduces reperfusion injury significantly and that both mechanisms are effectively inhibited in this model.

	Introduction

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Lung transplantation has become an established therapeutic option for end-stage pulmonary disease. ¹ Ischemia/reperfusion injury remains the major problem in the early phase after lung transplantation. Improved preservation and flushing technique have reduced morbidity of early graft dysfunction; however, severe ischemia/reperfusion injury still occurs in 10% of lung transplant recipients.

The pathophysiology of this type of injury has been extensively studied. Therapeutic strategies blocking only one of the redundant pathways of the nonspecific immune response showed limited success. ^2-5 Therefore, combined treatment suppressing more than one of the mediators of ischemia/reperfusion injury seems more promising.

The complement system as a part of the humoral first line of defense and a primary mediator of the inflammatory process is one of the major pathways leading to severe graft dysfunction following reperfusion after prolonged ischemia. In post-transplantation lung ischemia/reperfusion, complement activation may accelerate tissue injury either directly by complement factors or indirectly by complement-mediated neutrophil activation.

A long series of studies demonstrates that neutrophils contribute to the vascular dysfunction and permeability in the initial phase after reperfusion. sCR1sLe^x (AVANT Immunotherapeutics, Inc, Needham, Mass) combines the effect of human soluble complement receptor type 1 (sCR1) and sialyl Lewis X (sLe^x) in one molecule. It blocks complement activation and reduces leukocyte-endothelial adhesion. ⁶ In this study, the effect of sCR1sLe^x on post-transplantation graft function was evaluated in a small animal model of allogeneic single left lung transplantation after prolonged ischemia in comparison with untreated controls and recipients receiving sCR1 only.

	Materials and methods

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Weight-matched (200-250 g) male rats (donors: Brown Norway; recipients: Fischer F344) underwent orthotopic single left lung allotransplantation with a cuff technique used for the vessel anastomoses ⁷ and a conventional running suture for the bronchial anastomosis.

All animals received humane care in compliance with the European Convention of Animal Care. The protocol was approved by the local animal study committee.

Donor procedure
Each animal was anesthetized by intraperitoneal administration of pentobarbital (50 mg/kg) and was heparinized (500 IU/kg). A tracheotomy was carried out and the lungs were ventilated through a cannula (FIO₂ = 1.0) by a Harvard rodent ventilator (Harvard Apparatus, South Natick, Mass) at a tidal volume of 10 mL/kg. After division of the inferior vena cava and resection of the left appendix of the heart, a small silicone tube was inserted into the main pulmonary artery. Both lungs were flushed with 20 mL of low-potassium dextran solution (Perfadex; Xvivo, Göteborg, Sweden) ⁸ at a pressure of 20 cm H₂O. The trachea was tied in end-inspiration. The heart-lung block was removed and 14-gauge cuffs were placed around the pulmonary artery and vein. The vessels were inverted and tied onto the cuff. The lung was stored in low-potassium dextran solution at 4°C until implantation.

Recipient procedure
Transplantation was performed after 20 hours of cold ischemia (4°C). The recipient was anesthetized by breathing halothane in a glass chamber followed by intubation. Anesthesia was maintained with 2% halothane. A left lateral thoracotomy was performed in the fourth intercostal space. The left hilum was dissected. After the pulmonary artery and vein had been clamped with removable microclips, the pulmonary vein was opened, flushed with heparinized saline solution, and the cuff was inserted and fixed with 6-0 silk. In the same technique, the pulmonary artery was anastomosed. The native left lung was removed and the bronchial anastomosis performed with a running over-and-over stitch with 9-0 Monosof suture (Tyco Healthcare, Wollerau, Switzerland). The lung was first reventilated and then reperfused. A chest tube was inserted and the thoracotomy closed. The chest tube was removed after restoration of spontaneous breathing.

Assessment
The recipient animal was anesthetized by intraperitoneal administration of pentobarbital (50 mg/kg body weight).

Arterial blood gas analysis
Recipients were put to death 24 hours after reperfusion. Each animal was ventilated with an FIO₂ of 1.0, a frequency of 100 breaths/min, and a tidal volume of 8 mL/kg body weight by a tracheotomy. For functional assessment of the transplanted left lung, the right hilum was dissected and the right pulmonary artery and right main bronchus were occluded with microvessel clips. Five minutes after occlusion, a steady state was reached and an arterial blood gas sample was drawn from the thoracic aorta.

Myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances (TBARS)
Ventilation was the same as in donors. In these animals the lungs were flushed with 20 mL of saline solution through the pulmonary artery 24 hours after reperfusion. The transplanted lung was removed and snap-frozen in liquid nitrogen.

Study groups
In each group, 5 animals underwent transplantation for the evaluation of lung function by arterial blood gas analysis. In separate animals (n = 5/group), transplantation was done for the assessment of MPO and lipid peroxidation (TBARS).

Group I served as the control group, with no specific treatment. In group II recipients were treated with sCR1 (10 mg/kg), and in group III recipients received 10 mg/kg sCR1sLe^x. Both sCR1 and sCR1sLe^x were generously provided by AVANT Immunotherapeutics, Inc. Drugs were administered by intracardiac injection 15 minutes before reperfusion. For normal values of MPO and TBARS in rat lung, tissue samples of 4 animals were frozen directly after harvest.

Blood gas analysis
For assessment of arterial PO₂, a blood gas analyzer (AVL 993, AVL List GmbH, Graz, Austria) was used.

MPO assay
Lung samples were snap-frozen in liquid nitrogen and stored at –70°C until assay. Quantitative MPO activity was determined as previously described. ⁹ The frozen lung tissue (100 mg) was homogenized in 1 mL of 0.5% hexadecyltrimethylammonium bromide, 5 mmol/L ethylenediaminetetraacetic acid, and 50 mmol/L potassium phosphate buffer (pH 6.2) with a tissue grinder. The homogenate was centrifuged at 10,000g for 15 minutes at 4°C. The supernatant was assayed for total soluble protein by the method of Pierce Laboratories ¹⁰ and for MPO activity. Enzyme activity was measured spectrophotometrically. Then, 10 mg of 5-fold supernatant was combined with 0.6 mL Hanks bovine serum albumin solution, 0.5 mL of 100 mmol/L potassium phosphate buffer (pH 6.2), 0.1 mL of 0.05% H₂O₂, and 0.1 mL of 1.25 mg/mL o-dianisidine. Color development was stopped by addition of 1% NaN₃ after either 5 or 20 minutes at room temperature. The optical density was measured at 460 nm with a spectrophotometer (Kadas 100; Dr Lange AG, Zurich, Switzerland). Color development from 5 to 20 minutes was linear. Enzyme activity is expressed as change in optical density unit per milligram of tissue protein per minute (OD/mg/min).

TBARS
Donor and recipient lung samples were frozen immediately and stored at –70°C until assay. TBARS were measured according to the method of Ohkawa, Ohishi, and Yagi ¹¹ in 10% wet weight per volume homogenate. Aliquots (0.2 mL) of this homogenate were added to tubes containing 0.2 mL of 8.1% sodium dodecyl sulfate, 1.5 mL of 20% acetic acid solution adjusted to pH 3.5 with sodium hydroxide, and 1.5 mL of 0.8% solution of thiobarbituric acid. The mixture was brought to a volume of 4 mL by the addition of distilled water, heated at 95°C for 60 minutes, and then cooled with tap water. Next, 1 mL of distilled water and 5 mL of butanol/pyridine (15:1) were added (all chemicals by Fluka Chemie AG, Buchs, Switzerland). The solution was centrifuged at 4000 rpm for 10 minutes. The absorbance of the upper layer was measured at 532 nm with a spectrophotometer (Kadas 100; Dr Lange AG, Zurich, Switzerland). The TBARS levels were determined by reference to a standard curve of 1,1,3,3-tetramethoxypropane (Fluka Chemie AG, Buchs, Switzerland), and the results were expressed as picomoles of malondialdehyde per gram of wet lung.

Statistical analysis
All values are given as the mean ± standard error of the mean (SEM). Analysis of variance with planned comparison (contrast vectors) between the groups was applied. The STATISTICA 4.5 software (StatSoft, Tulsa, Okla) was used.

	Results

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Warm ischemic time in all transplantation groups was between 19.4 ± 1.0 and 20.8 ± 0.58 minutes, with no significant difference between groups (Table I).

Blood gas analysis
Twenty-four hours after reperfusion, arterial PO₂ was very low in control animals (group I, 56 ± 7 mm Hg). Treatment with sCR1sLe^x resulted in better graft function than in controls (383 ± 53 mm Hg, P = .000095) (Fig 1). Administration of sCR1 improved gas exchange to a significantly lesser extent than sCR1 sLe^x (243 ± 45 mm Hg, P = .0066 vs control; P = .031 vs sCR1 sLe^x).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Arterial PO2 (mm Hg) of the graft 24 hours after reperfusion (mean ± SEM).

View larger version (15K): [in this window] [in a new window]   Fig. 2. Myeloperoxidase activity (OD/mg/min) as measurement of neutrophil migration into the graft 24 hours after reperfusion (mean ± SEM).

TBARS
Lipid peroxidation was significantly elevated in control animals 24 hours after reperfusion as compared with lung tissue assessed directly after harvest (10.65 ± 0.54 vs 3.94 ± 0.75 pmol/g, P = .000005) (Fig 3). Grafts of recipients treated with sCR1 revealed a distinct reduction of TBARS (8.32 ± 0.89 pmol/g, P = .022 vs control). Treatment with sCR1sLe^x reduced lipid peroxidation significantly not only compared with controls (6.23 ± 0.38 pmol/g, P = .00021) but also compared with recipients that received sCR1 (P = .037).

View larger version (17K): [in this window] [in a new window]   Fig. 3. TBARS levels (pmol/g) in allograft tissue as measurement of lipid peroxidation 24 hours after reperfusion (mean ± SEM).

	Discussion

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

Complement is a proteolytic cascade system interacting with cells and is present in the blood plasma and other body fluids of all vertebrates. It mediates an inflammatory response by production of specific peptides with anaphylactic or chemotactic activity and the interaction with specific complement receptors on cell surfaces. The innate immune response is amplified by products of the complement components C3 and C5, which cause an increase in vascular permeability (C3a, C5a), leukocyte adhesion, and subsequent migration. Complement stimulates the synthesis of different proinflammatory cytokines. The final product of complement activation, the membrane attack complex, leads to direct membrane damage in target cells.

Complement receptor type 1 (CR1, CD35, C3b/C4b receptor) is a transmembrane glycoprotein expressed on erythrocytes and virtually all leukocytes. On phagocytes, CR1 is involved in the initial binding of particles coated with activated complement component 3 (C3b), which are subsequently ingested. CR1 is not only a cellular receptor, but also the most potent inhibitor of both the classical and alternative pathways of complement activation. Activated neutrophils and macrophages shed the extracellular portion of CR1 (soluble CR1, sCR1). ¹² It is more than 100-fold more effective than any other soluble complement regulatory proteins, for example, factor H, the physiologic cofactor for inactivation of C3b in plasma. ^13,14 Soluble CR1 accelerates the decay of the C3/C5 convertase complexes and participates in the degradation of C3b and C4b. ¹³ Inhibition of complement activation by administration of sCR1 protects against lung injury in different models of acute inflammatory response. ¹⁵ The inhibition of the nonspecific immune response after ischemia/reperfusion by administration of sCR1 in a model of myocardial infarction in rats demonstrated a beneficial effect. ¹⁴ Administration of sCR1 during unilateral lung transplantation in swine after prolonged ischemia completely inhibited complement activity and significantly reduced reperfusion edema, indicating the important role of complement activation for the development of ischemia/reperfusion injury. ¹⁶ The relevance of these findings has been confirmed recently by a clinical multicenter trial in patients undergoing lung transplantation. ¹⁷

Complement mediates activation and migration of neutrophils by C5a. Therefore, complement exerts the post-transplantation reperfusion injury not only by its effector proteins but also by stimulation of polymorphonuclear leukocytes. Besides ß-integrins and members of the immunoglobulin supergene family, selectins are adhesion molecules initiating leukocyte migration. These adhesion molecules are up-regulated in a number of different lung injuries. Specific inhibitors of neutrophil adhesion such as monoclonal antibodies and selectin ligands ¹⁸ and inhibitors of neutrophil selectin up-regulation as leumedins have been shown to reduce post-transplantation lung reperfusion injury in animal studies. In a rat model, combined administration of monoclonal antibodies against intracellular adhesion molecule-1, CD11a, and CD18 resulted in superior gas exchange 24 hours after reperfusion and reduced accumulation of neutrophils in the lung tissue. ¹⁹ Blockade of P-selectin by an anti–P-selectin immunoglobulin G antibody improved graft function and reduced polymorphonuclear leukocyte infiltration after rat lung transplantation. ²⁰

The oligosaccharide sLe^x is a ligand common to all selectins and therefore an attractive compound for the inhibition of selectin-dependent neutrophil adhesion. In a canine model of left lung allotransplantation after prolonged ischemia, administration of the carbohydrate sLe^x analog CY-1503 improved the graft's gas exchange (P < .01) and reduced neutrophil migration as assessed by MPO assay and neutrophil count in bronchoalveolar lavage fluids. ²¹

Recently, the glycoprotein product sCR1sLe^x has been synthesized by covalent post-translational modification of sCR1 with sLe^X glycosylation in a mammal cell line. ⁶ sCR1sLe^x maintains the complement blocking activity of sCR1, blocks P-selectin–mediated cellular adhesion, and binds to cell surface E-selectin in vitro. In vivo, its effects on experimental stroke and myocardial infarct size have been studied: Zacharowski and colleagues ²² subjected Wistar rats to 30 minutes of ischemia of the left anterior descending coronary artery, followed by 2 hours of reperfusion. Treatment with either sCR1 or sCR1sLe^x resulted in reduction of infarct size and less release of troponin T from injured myocytes. There was no clear superiority of sCR1sLe^x as compared with sCR1 alone; however, a longer ischemic time and reperfusion period might have emphasized the trend to a better improvement. In experimental cerebral ischemia in mice, pretreatment with sCR1sLe^x reduced infarct volume up to 11-fold in a dose-dependent manner and decreased intracerebral hemorrhage and neurologic deficit 24 hours after stroke. ²³ Infusion of sCR1 led to less reduction in infarct size and higher neurologic impairment. Interestingly, administration of both drugs after the onset of ischemia at the time of reperfusion also improved outcome, but to a lesser degree. Taking into account the clinical situation, in which treatment would probably be performed after the onset of reperfusion injury, further studies are needed to evaluate the effect of sCR1sLe^x in already established lung ischemia/reperfusion injury.

	Appendix: Discussion

Top Abstract Introduction Materials and methods Results Discussion Appendix: Discussion References

 
Dr Robert J. Keenan (Pittsburgh, Pa). What if you were to pretreat your donors in an effort to inhibit some of the adhesion of donor leukocytes as opposed to the adhesion of recipient leukocytes after transplantation?

Dr Stammberger. That is probably a good idea, but we have not done that yet. Taking into account that the effect of combined blockade of not only neutrophil adhesion but also complement activation is tested, it seemed more appropriate to treat the recipients.

	Footnotes

 
Read at the Eightieth Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, April 30–May 3, 2000.

	References

Top Abstract Introduction Materials and methods Results Discussion Appendix: 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): Ralph A. Schmid Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stammberger, U. Articles by Schmid, R. A. Search for Related Content PubMed PubMed Citation Articles by Stammberger, U. Articles by Schmid, R. A.