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J Thorac Cardiovasc Surg 1994;107:1183-1192
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Boston, Mass.
Supported in part by Public Health Service grants HL48675 (J.W.N.) and DK01977 (E.J.N.).
Received for publication July 30, 1993. Accepted for publication Nov. 2, 1993. Address for reprints: Ellis J. Neufeld, MD, PhD, Hematology, Enders 708, Children's Hospital, 300 Longwood Ave., Boston, MA 02115.
Abstract
Leukocyte adhesion to vascular endothelium is an early step in inflammatory damage to tissues. To investigate the expression of endothelial adhesion molecules in the inflammatory response associated with cardiopulmonary bypass, we measured messenger ribonucleic acid (mRNA) encoding the adhesion molecules E-selectin and intercellular adhesion molecule-1 in intraoperative samples of cardiac tissue and skeletal muscle from infants undergoing cardiopulmonary bypass. Atrial tissue samples were obtained before and after bypass from 11 children and paired samples of rectus abdominis muscle from 15. mRNA was analyzed by ribonuclease protection with the use of nonmuscle actin as an internal control. Atrial E-selectin mRNA levels increased from before to after bypass (median increase 3.5-fold, p = 0.0002) in each of nine patients tested, and atrial intercellular adhesion molecule-1 mRNA increased in seven of nine patients (median, 2.1-fold, p = 0.025). In skeletal muscle, E-selectin mRNA increased in 11 of 12 patients (median 4.3-fold, p = 0.0018), and intercellular adhesion molecule-1 mRNA levels increased in 13 of 13 patients (median 3.2-fold, p = 0.013). E-selectin and intercellular adhesion molecule-1 induction in skeletal muscle occurred with or without circulatory arrest. We conclude that adhesion molecule mRNA induction occurs in cardiac and noncardiac tissue during cardiopulmonary bypass in man. (J THORACCARDIOVASCSURG1994;107:1183-92)
Reparative operations for most congenital heart defects require a period of myocardial ischemia and the use of cardiopulmonary bypass. There is increasing evidence that the damaging effects of both ischemia-reperfusion and bypass are related to inflammatory processes. A critical mechanism of tissue damage during inflammation is the adhesion of leukocytes to the vascular endothelium via specialized endothelial and leukocyte cell surface adhesion molecules. Animals treated with monoclonal antibodies directed at the leukocyte adhesion molecule CD11/CD18, or at its endothelial ligand, intercellular adhesion molecule-1 (ICAM-1), during cardiac ischemia and reperfusion have reduced myocardial damage and improved postoperative cardiac function.
1-4 Data are limited on the role of adhesion molecules in bypass-related morbidity and in human vascular injury from either ischemia-reperfusion or cardiopulmonary bypass.
The purpose of this study was to assess in human beings whether cardiopulmonary bypass induces the myocardial expression of messenger ribonucleic acid (mRNA) for endothelial adhesion molecules implicated in neutrophil migration and to determine the relative contributions of ischemia-reperfusion versus the general inflammatory effects of cardiopulmonary bypass to any observed changes in expression. We chose to study two endothelial adhesion molecules thought to be regulated at the level of mRNA induction: E-selectin and ICAM-1. E-selectin, which binds to carbohydrate ligands on neutrophils, is nearly undetectable in resting human umbilical vein endothelial cells and is induced in response to cytokines such as tumor necrosis factor-
(TNF-) or interleukin-1 over a time course of 2 to 4 hours. 5-7 ICAM-1 is expressed at low levels on unstimulated endothelial cells. Its mRNA is induced dramatically over the course of 1 to 2 hours on treatment with cytokines. 8,9 ICAM-1 is also expressed in canine cardiac myocytes on induction with inflammatory mediators. 10-13 The counter-receptors for ICAM-1 are CD11a/CD18 (LFA-1), constitutively expressed on all leukocytes, and CD11b/CD18 (Mac-1), which is expressed on neutrophils, monocytes, and natural killer cells. 14 We measured cardiac expression of mRNA encoding E-selectin and ICAM-1 before and after myocardial ischemia and reperfusion during cardiopulmonary bypass. To control for the inflammatory effects of bypass, we also measured expression of these molecules in skeletal muscle from patients undergoing cardiopulmonary bypass with or without a period of total body ischemia produced by deep hypothermic circulatory arrest. Our study population comprised infants and children undergoing reparative heart operations.
Pediatric cardiac operations with hypothermic cardiopulmonary bypass offer a unique opportunity to study bypass-related injury in human cardiac tissue under well-defined circumstances. In these patients, hypothermic cardiopulmonary bypass is instituted and the aorta is crossclamped, arresting coronary blood flow. In some patients, technical considerations require the institution of deep hypothermic circulatory arrest, during which the cardiopulmonary bypass is suspended for periods up to 70 minutes, producing whole-body ischemia. After the intracardiac portion of the procedure, the aortic crossclamp is removed, restoring coronary perfusion, and the patient is rewarmed with use of the bypass circuit. The period of aortic crossclamping represents the duration of cardiac ischemia, because reperfusion commences with the resumption of coronary blood flow. With the use of a sensitive and specific RNase protection assay, we present here the first data from human beings that demonstrate a postoperative increase in expression of ICAM-1 and E-selectin mRNA in atrial tissue and skeletal muscle of patients undergoing hypothermic cardiopulmonary bypass.
MATERIALS AND METHODS
Patient selection
Study design and consent forms were approved by the Children's Hospital Institutional Review Board. Tissues were obtained from patients undergoing cardiac operations for repair of a variety of structural lesions. Selection criteria included (1) no recent intracardiac operations, (2) no known preexisting vascular disease, and (3) informed consent of the parents.
Hypothermic cardiopulmonary bypass and myocardial protection
Patients were cooled with ice bags and cooling blankets while being prepared for cardiopulmonary bypass. Cannulas were inserted in the ascending aorta and right atrium, and core cooling was begun with bypass. The aorta was crossclamped and cold cardioplegic solution infused into the aortic root. The cardioplegic solution used was Plegisol (Abbott Laboratories, Chicago, Ill.). The electrolyte content per liter of this solution is Ca 2.4 mEq, Mg 32 mEq, K 16 mEq, Na 110 mEq, and C1 160 mEq. The solution was buffered with 10 ml 8.4% sodium bicarbonate injection (Abbott) per liter just before administration. Filtered 100% oxygen (250 cc) was injected directly into the plastic bag containing the cardioplegic solution. The solution was cooled to 4° C just before use. In those patients whose procedure required total circulatory arrest, perfusion was discontinued when the core temperature reached approximately 18° C and the patient's blood was drained into the pump reservoir. At the end of the procedure the aortic crossclamp was removed and the patient rewarmed during bypass.
Tissue collection
We obtained samples of atrial tissue (average size 30 mm3) from right or left atrium before and at the conclusion of cardiopulmonary bypass. Prebypass atrial tissue was obtained at the site of cannulation (right atrial appendage), and postbypass samples were obtained either at the site of venting (left atrial appendage, at the end of bypass) or at sites of right or left atrial line placement. These sites were chosen to ensure that the postbypass specimen was fresh, intact myocardium, rather than damaged tissue from the cannulation margin. Samples of skeletal muscle (rectus abdominis) of similar size were obtained from the margins of the incision before and after bypass. We recorded times of sample removal and times of initiation and termination of cardiopulmonary bypass, aortic crossclamping, and circulatory arrest (when applicable). Tissue samples were frozen immediately in liquid nitrogen. Samples were stored at -80° C or in liquid nitrogen until processing.
RNA extraction
Frozen tissue samples on dry ice were crushed with use of a Bessman steel piston apparatus (VWR, Boston, Mass.) and immediately immersed in RNAzol-B (Tel-Test "B," Friendswood, Tex.) and RNA isolated by the method of Chomczynski and Sacci. 15 RNA pellets were resuspended in water with 0.5% sodium dodecyl sulfate. Twenty percent of each sample was used for quantitation by absorption at 260 nm.
Construction of complementary deoxyribonucleic acid (cDNA) templates for riboprobe synthesis
We prepared templates of different lengths for ICAM-1, E-selectin, and 
-actin (as an internal control) to allow simultaneous hybridization of all three riboprobes with each sample (multiplex RNase protection analysis). The ICAM-1 full-length probe measured 220 bases, and the complementary (protected) sequence was 181 bases. The full-length E-selectin probe was 323 bases, and the protected sequence 255 bases. The -actin probe was 145 bases full-length and 140 bases protected. cDNAs were obtained for human E-selectin 6 (courtesy of Dr. M. Bevilacqua) and ICAM-1 16 (courtesy of Dr. T. Springer). By polymerase chain reaction (PCR), shorter sequences of appropriate length for RNase protection were amplified with convenient flanking restriction sites and cloned into the polylinker of pBluescript II KS (Stratagene, LaJolla, Calif.). For ICAM-1 the PCR product included bases 785 to 966 of the full length cDNA, flanked by 5' Pst I and 3` BamH I sites. After insertion into pBluescript a 29-base pair Xho I-EcoR I sequence was excised from the 5' region of the polylinker, filled in with Klenow fragment of DNA polymerase (Boehringer-Mannheim, Indianapolis, Ind.) and religated 17 to produce a 39-base distance from the T3 transcriptional initiation site to the ICAM-1 sequence. The E-selectin PCR product included bases 397 to 652 and was cloned between the EcoR I and BamH I sites of pBluescript. The -actin template was obtained from Dr. M. C. Simon; it represents a portion of the 3' untranslated region of the human -actin gene cloned into the plasmid pSP64. 17,18
Riboprobe synthesis
RNase protection assays were done as described. 32P-labeled RNA probes were synthesized by runoff transcription from linearized templates in Promega transcription buffer (Promega, Madison, Wis.) using the appropriate RNA polymerase: T3 for ICAM-1 and E-selectin or SP6 for -actin (Boehringer) to produce antisense RNA. ICAM-1 and E-selectin templates described previously herein were linearized with BamH I. pSP64-actin was linearized with Hinf I.
RNase protection
For each patient, equal amounts of prebypass and postbypass sample RNA were analyzed in parallel (Table I). For positive controls, human umbilical vein endothelial cells were stimulated for 1 hour with 100 units/ml of human recombinant TNF- (courtesy of Dr. J. Bischoff) and 1 µg aliquots of human umbilical vein endothelial cell RNA were assayed. RNA was precipitated and resuspended in hybridization buffer consisting of 40 mmol/L PIPES (pH 6.4), 1 mmol/L ethylenediaminetetraacetic acid, and 0.4 mol/L NaCl in 80% deionized formamide. To each sample, we added 500,000 cpm of riboprobe for ICAM-1 and/or E-selectin, plus 40,000 cpm of actin riboprobe as an internal control. The samples were then heated to 90° C for 5 minutes and allowed to anneal at 37° C overnight. The samples were then treated for 15 minutes at 37° C with an RNase mixture consisting of 10 mmol/L Tris-Cl pH 7.4, 5 mmol/L ethylenediaminetetraacetic acid, 300 mmol/L NaCl, 40 µg/ml RNase A (Boehringer), and 2 U/ml RNase T1 (Boehringer). The digestion was stopped by incubation with 250 µg/ml proteinase K (Boehringer) in 0.5% sodium dodecyl sulfate for 15 minutes at 37° C, followed by phenol extraction, chloroform extraction, and ethanol precipitation. Samples were analyzed on a 4% acrylamide-urea sequencing gel. 19 Fixed gels were exposed to X-OMAT AR film (Kodak, Rochester, N.Y.) or PhosphorImager screen (Molecular Dynamics, Sunnyvale, Calif.) overnight. Size standards were pBR322 fragments from Hinf I digests, end-labeled with [- 32P] adenosine triphosphate and polynucleotidekinase, after treatment with alkaline phosphatase. 19
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Tables I and II).
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RESULTS
Patient population, sample collection, and RNA yield
A total of 20 patients were studied. Among these, we obtained adequate atrial tissue samples before and after bypass from 11 patients and muscle samples from 15. The characteristics of these patients are listed in Tables I and II. The patients' ages ranged from 7 days to 6 years (median age 5 months). Their diagnoses and surgical procedures are listed in the tables; they reflect the complex mix of cardiac lesions seen at this center. Median duration of bypass was 153 minutes (range 42 to 229 minutes); of aortic crossclamping 79 minutes (range 12 to 155 minutes); and of time from onset of cardiac reperfusion to excision of the postbypass sample 68 minutes (range 35 to 187 minutes). Twelve patients had hypothermic circulatory arrest; the median duration was 36 minutes (range 10 to 65 minutes). Yields of total RNA from atrial and skeletal muscle samples in the study ranged from 1 to 48 µg. Postbypass atrial samples were typically smaller pieces of tissue and therefore yielded less RNA. For each patient, equal amounts of RNA were used from prebypass and postbypass samples (Tables I and II).
Multiplex RNase protection analysis
Results of a pilot experiment on RNA from TNF-–stimulated human umbilical vein endothelial cells are shown in Fig. 1, A. Unique protected bands for each of the molecules analyzed were easily distinguished from undigested probe and from each other (ICAM-1 lanes 1 versus 2; E-selectin lanes 3 versus 4; -actin lanes 5 versus 6). This allowed us to mix the three probes and assay all three molecules in single samples (lane 7). Some of the earliest patients' samples were hybridized with either ICAM-1 or E-selectin plus actin (Table I, patient Nos. 2, 4, 10, 11; Table II, patient Nos. 1, 2, 6, 8, 16). Subsequently, multiplex assays were used for simultaneous analysis of ICAM and E-selectin (plus actin control) in all remaining patients.
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-actin) as an internal control for mRNA quantitation. Because equal amounts of total RNA were used for each patient sample pair, the -actin signal also served as a control for recovery of mRNA. Comparison of actin bands revealed consistent RNA loading and recovery for most sample pairs (Fig. 1, B, lanes 1 versus 2, 3 versus 4, 5 versus 6). Ratios of actin mRNA levels in postbypass versus prebypass samples were not significantly different from 1, though some variation was observed (for example, patient 7 in Table I), presumably because of differences in gel loading or RNA quantitation.
Induction of adhesion molecules in human atrium
E-selectin message increased in postischemic samples from all nine patients in whom atrial E-selectin was measured. Degree of induction ranged from 1.5 to 8.8-fold (median 3.5; p = 0.0002, Table I). ICAM-1 mRNA increased in seven of nine patients studied (Table I). Postbypass-to-prebypass atrial ICAM-1 ratios ranged from 0.6 to 8.8 (median increase 2.1-fold; p = 0.025).
There was no association in atrial tissue between degree of induction and duration of cardiopulmonary bypass, aortic crossclamp time, or reperfusion time (time from removal of aortic crossclamp to excision of postbypass tissue sample). However, there was a significant correlation between patient age and degree of ICAM-1 induction, with induction increasing with age (r = 0.83, p < 0.006; Fig. 3).
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Table II). ICAM-1 message increased in each of the 13 patients studied. Postbypass-to-prebypass ICAM-1 ratios ranged from 1.3 to 10 (median increase 3.2-fold; p = 0.013). The degree of induction of either molecule was not significantly associated with duration of bypass, aortic crossclamp time, reperfusion time, or patient age.
Of the 15 patients from whom skeletal muscle samples were obtained, 11 were subjected to deep hypothermic circulatory arrest (Table II). Duration of deep hypothermic circulatory arrest ranged from 10 to 65 minutes (median 36 minutes). There was no correlation between the duration of deep hypothermic circulatory arrest and degree of E-selectin or ICAM-1 mRNA induction in skeletal muscle; indeed, of the four patients not subjected to the whole-body ischemia of deep hypothermic circulatory arrest, all showed induction of both molecules (E-selectin from 1.4 to 13-fold after bypass; ICAM-1 1.7 to 6.3-fold; Table II). We conclude that E-selectin and ICAM-1 mRNA induction occurs in the setting of pediatric cardiopulmonary bypass and that bypass alone, independent of ischemia and reperfusion, may be sufficient to cause this induction, at least in skeletal muscle. Although the number of patients subjected to bypass without deep hypothermic circulatory arrest in this study was small, observation of adhesion molecule mRNA induction in the skeletal muscle of all four demonstrates that ischemia-reperfusion is not a necessary condition for induction.
DISCUSSION
Inflammation plays a central role in bypass-related and ischemia-reperfusion injury. A crucial step in the development of inflammatory damage is the adhesion of leukocytes to the vascular endothelium via specific interactions between endothelial and leukocyte cell surface adhesion molecules. Adhesion of leukocytes to damaged endothelium contributes to obstruction of small vessels and is followed by transendothelial migration of leukocytes into tissues, with subsequent release of toxic oxygen radicals and inflammatory cytokines. 20-23 The present study offers the first evidence of increased expression of two important endothelial adhesion molecules in human cardiac tissue and skeletal muscle after cardiopulmonary bypass. Messenger RNAs for ICAM-1 and E-selectin were significantly induced in a series of pediatric patients undergoing cardiac operations for a wide variety of congenital cardiac lesions. The degree of induction of ICAM-1 in atrial tissue varied directly with patient age. Induction was observed in skeletal muscle with cardiopulmonary bypass, with or without the use of total circulatory arrest.
It has long been recognized that edema develops in patients undergoing cardiopulmonary bypass because of increased vascular permeability. 24 The extracorporeal circulation of blood over the artificial surfaces of the bypass circuit activates the complement, 25 coagulation, and kallikrein-kinin cascades and activates platelets and leukocytes. 26,27 Levels of interleukin-1 are increased in patients after cardiopulmonary bypass 28; interleukin-1 in turn induces expression of vascular adhesion molecules ICAM-1 and VCAM-1 and activates CD11/CD18 on leukocytes. Surface expression of CD11b is increased on neutrophils during bypass. 27 P-selectin, an adhesion molecule, which is stored preformed in granules in platelets and endothelial cells, is expressed on the surface of circulating platelets during bypass, 27,29,30 and thrombin formed during activation of the coagulation cascade activates expression of P-selectin on endothelial cells. 31 Increased levels of interleukin-8, a neutrophil chemoattractant, are detectable in the blood of patients after cardiopulmonary bypass. 32 Our data describing induction of mRNA for ICAM-1 and E-selectin in heart and skeletal muscle of children undergoing cardiopulmonary bypass provide further evidence implicating vascular adhesion molecules in bypass-related injury.
Cardiopulmonary bypass alone appears sufficient to induce ICAM-1 and E-selectin, at least in skeletal muscle. In cardiac muscle, ischemic injury during bypass may contribute to this induction, and adhesion molecules probably contribute in turn to myocardial ischemia reperfusion injury in these patients. Previous studies in animals have demonstrated the importance of adhesion molecules in mediating such injury. In a canine model of coronary artery occlusion, animals treated with the anti-CD11b monoclonal antibody 904 during ischemia had significant reduction in the mean size of myocardial infarct and the accumulation of neutrophils in the ischemic tissue compared with results in control animals. 1 Similarly, cats subjected to 90 minutes of myocardial ischemia induced by occlusion of the left anterior descending coronary artery followed by 4.5 hours of reperfusion demonstrated significantly less myocardial necrosis, lower myeloperoxidase activity, and less neutrophil adherence to ischemic coronary endothelium when treated during the period of ischemia with RR1/1, a monoclonal antibody to ICAM-1. 4 A recent study of hypothermic ischemia and reperfusion in isolated blood-perfused neonatal lamb hearts has demonstrated the physiologic importance of myocardial injury mediated by ICAM-1 and CD18 in the surgical setting: hearts treated with an anti-CD18 monoclonal antibody before a 2-hour period of cardiac arrest at 15° C demonstrated better left ventricular function and increased coronary blood flow after reperfusion. 3 In addition to these studies of myocardial injury, others have shown that monoclonal antibodies to CD18 or ICAM-1 significantly reduce organ and tissue injury in models of hemorrhage-reperfusion 33,34 and vascularocclusion-reperfusion. 2,35-37
In vitro studies reveal induction of E-selectin and ICAM-1 mRNA in human umbilical vein endothelial cells by interleukin-1 and TNF within 1 to 4 hours. 6,38 In addition, isolated canine cardiac myocytes have been shown to express ICAM-1 on stimulation either with cytokines 11 or with postreperfusion cardiaclymph. 13 Furthermore, increased levels of ICAM-1 mRNA have been detected in canine myocardium subjected to ischemia and reperfusion. 11 These observations suggest that the ICAM-1 induction described here could be occurring in atrial myocytes, as well as in vascular endothelium. Our data support a role for early ICAM-1 induction in neutrophil-mediated myocardial cellular damage during cardiopulmonary bypass and/or reperfusion, 12 as well as in the regulation of leukocyte-endothelial adhesion. Finally, one previous study has demonstrated increased E-selectin myocardial mRNA expression after 24 hours following ischemia and reperfusion in a canine model. 39 The present study provides the first evidence of rapid induction of E-selectin in tissues after cardiopulmonary bypass. This finding could be consistent with an important role for E-selectin in early reperfusion injury in human beings.
The importance of a correlation between patient age and ICAM-1 induction in atrial tissue is uncertain. The differences could be related to the biologic process of ischemic injury in infants, but might also reflect differences in bypass techniques or other surgical variables. The small number of patients limited our power to assess the relationship between induction of adhesion molecules and intraoperative or postoperative variables (for example, duration of cardiac ischemia or postoperative cardiac function). In addition, all patients were subjected to hypothermia, making it impossible to assess independently the importance of this variable. However, previous studies in experimental animal models have shown similar induction of adhesion molecules during normothermic bypass. 27-30
The minute size of the individual tissue samples necessitated that each piece of tissue be used in its entirety for RNase protection. In principle, RNA detection by in situ hybridization might determine exactly which cell types are responsible for increased mRNA levels in tissue pieces. Further immunohistochemical analysis will be required to determine the cellular localization of newly synthesized proteins. On the basis of animal studies, we postulate that E-selectin induction will be limited to endothelium, whereas ICAM-1 expression may be increased both in endothelial cells and in myocytes.
Human studies of adhesion molecule induction in the setting of cardiopulmonary bypass form an important link between elegant studies of these molecules in animals and eventual use of anti–adhesion molecule therapy in this clinical setting. Demonstration of the induction of two important adhesion molecules in the human heart represents a first step in this direction. Future work will attempt to define the specific cellular sites of increased adhesion molecule synthesis, thereby allowing us to determine the relative contributions of myocytes and endothelium in the induction of ICAM-1. In addition, larger studies of this kind in human beings will help to further elucidate the clinical significance of these findings, through investigation of correlation between adhesion molecule expression, intraoperative variables, and postoperative patient course.
Acknowledgments
We thank Dr. Stephen Roth and Dr. Joyce Bischoff for advice and reagents.
Footnotes
From the Departments of Cardiology, Cardiac Surgery, a Anesthesia, b and Medicine, c Children's Hospital; Dana Farber Cancer Institute d; and Harvard Medical School, Boston, Mass. 
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