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Ann Thorac Surg 1996;62:1295-1300
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Blockade of Selectin-Mediated Leukocyte Adhesion Improves Postischemic Function in Lamb Hearts

Departments of Cardiovascular Surgery, Pediatrics, Cardiology, and Anesthesia, Children's Hospital and Harvard Medical School, Boston, Massachusetts

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Leukocyte-endothelial interactions appear to have an important role in ischemia/reperfusion injury and are mediated by specific leukocyte and endothelial adhesion molecules. The selectins are adhesion molecules found on leukocytes (L-selectin) and endothelium (P and E selectin) that bind to oligosaccharide ligands containing fucose and sialic acid to mediate leukocyte rolling on the endothelium. Fucoidin is a nontoxic sulfated fucose oligosaccharide derived from seaweed that blocks the selectins.

Methods. `We tested the effects of fucoidin in an isolated blood-perfused neonatal (age range, 3 to 7 days; mean age, 4.3 days) lamb heart model undergoing 2 hours of cold cardioplegic ischemia. In group F (n = 8) fucoidin (30 mg/L) was added at initial reperfusion. Group C (n = 9) received only cardioplegia with no reperfusion intervention. Isovolumic maximum developed pressure and the maximum positive and negative first derivatives of pressure were measured using a catheter-tip transducer in an intraventricular balloon before ischemia and at 30 minutes of reperfusion. Coronary blood flow, myocardial oxygen consumption, and white blood cell counts in the circulating blood were also measured.

Results. Percent recoveries of baseline maximum developed pressure and maximum positive and negative first derivatives of pressure in group F (86% ± 5%, 81% ± 10%, and 74% ± 8%, respectively; mean ± standard deviation) were higher than in group C (77% ± 5%, 70% ± 9%, and 65% ± 6%; p < 0.05). Group F postischemic coronary blood flow was greater (190% ± 35%) than in group C (102% ± 10%; p < 0.05). Recovery of myocardial oxygen consumption in group F (86% ± 14%) was greater than group C (72% ± 11%; p < 0.05). Postischemic white blood cell count in group F (88% ± 4%) was greater than in group C (81% ± 5%; p < 0.05).

Conclusions. Selectin blockade with fucoidin resulted in better recovery of left ventricular function, coronary blood flow, and myocardial oxygen consumption after cold ischemia, despite a higher circulating white blood cell count. These data support the hypothesis that endothelial-leukocyte interactions play an important role in ischemia/reperfusion and suggest that selectin blockade may be a useful therapeutic strategy.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1300.

Recent studies have revealed that the interaction between leukocytes and vascular endothelial cells plays an important role in various inflammatory disorders including the reperfusion injury that occurs after ischemia [1, 2]. Various adhesion molecules on both leukocytes and vascular endothelium are thought to be responsible for the initial rolling and then the subsequent firm adhesion of leukocytes to the endothelial cell [3]. The selectins (L- and P-selectin) are adhesion molecules that recognize fucosylated carbohydrate ligands, and the selectins appear to be responsible for the initial rolling of leukocytes along the endothelial surface [4–6]. This rolling of leukocytes occurs at the onset of inflammation as the precursor to leukocyte adhesion and transendothelial leukocyte migration [6]. Prevention of leukocyte adhesion to the endothelium is a potential strategy to prevent reperfusion injury to the myocardium after ischemia, and antiadhesion treatment directed at appropriate adhesion molecules has been shown to offer protection from the effects of ischemia and reperfusion in other models [7–14]. Many of these prior studies have demonstrated that inhibition of the firm adhesion of leukocytes to endothelium, which is mediated by integrin-ICAM-1 interactions, has a beneficial effect on ischemia-reperfusion injury [7–12], but the impact of inhibiting the earliest leukocyte-endothelial interactions, which are selectin-mediated, is less clear, particularly where the ischemia occurs under hypothermic conditions.

Fucoidin is a nontoxic oligosaccharide derived from seaweed that blocks the function of the selectin group of leukocyte (L-selectin) and endothelial (P-selectin) adhesion molecules [5]. In the current studies, the effect of administration of fucoidin during reperfusion on the injury resulting from hypothermic myocardial ischemia and reperfusion was tested using an isolated blood-perfused neonatal lamb heart model.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experimental Preparation
All animals in this study have 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).

An isolated, blood-perfused heart model, which has been described in detail in previous studies from our laboratory, was used for this study [11, 15, 16]. A total of 17 juvenile lambs (body weight, 4.5 ± 0.9 kg; age, 4.3 ± 1.2 days) were studied. After intramuscular ketamine (40 mg/kg) injection, the animals were intubated and mechanically ventilated with inhalation of a 1:1 mixture of oxygen and nitrous oxide and 0.5% halothane. After a median sternotomy and systemic heparinization (2,000 units), a 20F arterial cannula was inserted retrograde into the brachiocephalic artery. Coronary perfusion was maintained with heparinized homologous blood using a roller pump (Coronary Perfusion Pump; Olson Medical Products Inc, Ashland, MA) and a bubble oxygenator (Bentley Bio-2 Infant Blood Oxygenator; Baxter Healthcare Corp, Irvine, CA). The perfusate was oxygenated with a mixture of 20% O₂, 5% CO₂, and 75% N₂, and coronary perfusion pressure was maintained constant at 60 mm Hg throughout the experiment except during the preparation period (70 mm Hg). After the heart was excised, it was placed on a temperature-controlled water bath. The temperature of the perfusate and the water bath were maintained at 37°C except during the hypothermic period. Both superior and inferior venae cavae were ligated, and all of the coronary venous return was collected through a 24F venous cannula, which was inserted into the right ventricle retrograde via the pulmonary artery. To sample the coronary venous blood, a 3.5F catheter was inserted into the hemiazygos vein, which drains to the coronary sinus in this species.

A latex balloon containing a pressure transducer (SPC-350; Millar Instruments Inc, Houston, TX) was placed within the left ventricle (LV) via the apex to measure LV function. A Foley balloon catheter (10F) was inserted into the left atrium to prevent the LV balloon from herniating into the left atrium and to vent blood and air from the LV.

Measurements
Perfusion pressure was monitored by a catheter contained in the arterial cannula. Coronary blood flow (CBF) was measured by a 0.6-mm in-line type electromagnetic flow probe and flowmeter (FF-060T and MFV-3100; Nihon Kohden, Tokyo, Japan), which was connected to the cannula that had been inserted into the pulmonary artery. This flow represents the CBF because this is the only venous blood reaching the right ventricle.

Left ventricular function was measured during isovolumic contraction by inflating the intraventricular balloon with 0.5-mL increments of saline solution until an LV end-diastolic pressure of 20 mm Hg was reached. Left ventricular pressure and its first derivative (dp/dt) were recorded at each volume. Left ventricular function was evaluated by measuring the maximum developed pressure, maximum LV positive dp/dt, and maximum LV negative dp/dt.

Arterial and venous blood were collected in the beating, nonworking state. The hemoglobin concentration and the oxygen saturation were measured with a blood gas analyzer (Stat profile 9; NOVA Biomedical, Waltham, MA). Myocardial oxygen consumption was calculated as (arterial O₂ content - venous O₂ content) x CBF/myocardial wet weight, where O₂ content (mL/dL) = 1.39 x hemoglobin x O₂ saturation/100 + 0.0031 x O₂ tension. Myocardial oxygen consumption was measured before ischemia and 5, 15, 30, and 60 minutes after reperfusion.

Circulating white blood cell counts were measured with an automated analyzer. (Technicon H-1; Miles, Tarrytown, NY).

Experimental Protocol
Baseline measurements were made after a 20-minute equilibrium period after isolation of the heart. Immediately after the baseline measurement, both the perfusate and water bath were cooled to 15°C over 10 minutes. Then, the heart was arrested by infusion of 20 mL/kg body weight of cardioplegic solution over 2 minutes. During cardioplegic arrest, myocardial temperature was maintained at 10°C by topical cooling, and a second dose of cardioplegic solution (10 mL/kg) was given 60 minutes after cardiac arrest. The composition of cardioplegic solution was 0.45% sodium chloride and 2.5% dextrose solution with 20 mEq/L of potassium chloride and 6 mEq/L of sodium bicarbonate (pH 7.4 at 37°C, osmolarity = 360 mOsm/L).

After 2 hours of cardioplegic arrest, the isolated heart was reperfused with the perfusate at room temperature (25°C) and then rewarmed to 37°C over 25 minutes. Mean coronary perfusion pressure was maintained at 20 mm Hg during the first 5 minutes, raised to 40 mm Hg during the second 5 minutes, and then kept at 60 mm Hg until the end of experiment [16].

During the first 15 minutes of the reperfusion period, the oxygenator was bubbled with high oxygen (95% O₂, 5% CO₂) to imitate the arterial blood gas conditions in the clinical situation. Thereafter the gas was changed to 20% O₂, 5% CO₂, and 75% N₂.

Experimental Groups
Two groups of hearts were studied. In group F (n = 8), fucoidin (Sigma, St. Louis MO) was added to the blood perfusate in the reservoir just before the start of reperfusion to achieve a concentration of 30 mg/L. In group C (n = 9), unmodified blood was used for reperfusion.

Statistics
All values were expressed as mean ± standard deviation and analyzed by a statistical analysis software package (SPSS; SPSS Inc, Chicago, IL). Unpaired Student's t test was used to compare the differences between the percent recovery of baseline values between the two groups, and analysis of variance was used to compare the differences between preischemic and postischemic values. A p value less than 0.05 was considered significant.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Baseline Measurements
There were no significant differences between these two groups in baseline measurements (Table 1).

View larger version (50K): [in this window] [in a new window]   Fig 1. . Percent recovery of left ventricular function. Open bars indicate group C. Solid bars indicate group F. (DP = developed pressure; max +dp/dt = maximum positive value of first derivative of left ventricular pressure; max -dp/dt = maximum negative value of first derivative of left ventricular pressure; REP30 = 30 minutes of reperfusion; REP60 = 60 minutes of reperfusion; *p < 0.05 versus group C; **p < 0.005 versus group C.)

View larger version (33K): [in this window] [in a new window]   Fig 2. . Percent of baseline values of coronary blood flow (CBF) after reperfusion. (*p < 0.05 versus group C.)

Water Content
Myocardial water content of both groups showed no statistical difference at the end of the experiment (after 60 minutes of reperfusion) (see Table 3).

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The current study shows that infusion of fucoidin only during reperfusion has a protective effect in the isolated, blood-perfused neonatal lamb heart subjected to cold ischemia and reperfusion. This model closely simulates the hypothermic cardiac arrest and reperfusion conditions occurring during most pediatric cardiac surgical procedures. The mechanical function of the LV was well preserved in the group receiving fucoidin, and recovery of CBF and myocardial oxygen consumption were better in the fucoidin group. The decrease in white blood cell count in the circulating blood was greater in group C than in group F, suggest that the adhesion of leukocytes to either the coronary vasculature or the oxygenator was somewhat reduced in group F.

The processes by which ischemia and reperfusion result in tissue injury are now known to involve not only anoxic damage during ischemia, but an important additional injury during reperfusion as blood flow to the ischemic tissue is reestablished [1, 2, 17]. Recent studies have demonstrated that reperfusion injury involves various parts of the inflammatory response and that leukocyte-endothelial interactions have a central role in the inflammatory process [1, 2, 8–14]. Specific adhesion molecules on both leukocytes and endothelial cells have been identified and shown to mediate these interactions [1, 2]. Once leukocytes are adherent to the endothelium, these activated leukocytes release products such as oxidants, proteases, and cytokines that directly cause endothelial damage [1–3]. In addition, microvascular occlusion by leukocyte plugs may also occur, leading to the "no-reflow" phenomenon [18]. After adherence to the endothelium, leukocytes subsequently can transmigrate into the tissues and contribute to tissue damage by releasing a variety of inflammatory mediators and cytotoxic substances [1, 2].

The initial process in leukocyte adhesion to the endothelium is leukocyte rolling along the endothelial surface [3, 6, 19]. This rolling process is mediated by a specific group of adhesion molecules known as selectins [6, 19]. L-selectin is constitutively expressed on unactivated leukocytes and P-selectin is normally stored in Weibel-Palade bodies in the endothelium and can be rapidly expressed on the surface of endothelium [3, 4]. P-selectin is also found on activated platelets and is involved in leukocyte-platelet interactions [3, 4]. Other groups of adhesion molecules of the beta-integrin (CD11a/CD18, CD11b/CD18) and immunoglobulin families (ICAM-1, ICAM-2) are necessary for later firm adhesion between leukocytes and endothelium, which follows the initial leukocyte rolling [1–3]. The selectins appear to be necessary for the initial adhesion and rolling of leukocytes on the endothelium under physiologic shear stress [6, 19, 20]. Leukocyte rolling appears to be required for the later firm adhesion between leukocytes and endothelium, which is mediated by the integrin-ICAM interactions [19–21]. Severe hypoxia and reoxygenation alone can cause endothelial cells to express P-selectin and induce leukocyte rolling in vitro [22].

Anti-adhesion therapy is a new approach to alter the ischemia and reperfusion process. This therapy is aimed at preventing the interactions between activated leukocytes and endothelium that allow the leukocytes to adhere to and transmigrate through the endothelium and cause both vascular and tissue injury. One such anti-adhesion approach is the use of monoclonal antibodies against specific adhesion molecules. Binding between the CD11b/CD18 complex (Mac-1) and ICAM-1 is of critical importance for the process of firm leukocyte adhesion to vascular endothelium and the subsequent transmigration of leukocytes through the vessel wall [1, 3, 21]. Antibodies that block the function of these adhesion molecules have been shown to reduce myocardial ischemia/reperfusion injury [7–12]. Ma and associates have demonstrated that both anti-ICAM-1 [8] antibody and anti-CD18 antibody [9] reduce infarction size and preserve coronary vascular and ventricular mechanical function in a feline normothermic ischemia reperfusion model. Simpson and colleagues [10] reported that an F (ab) 2 fragment of an anti-CD11b/CD18 antibody had a protective effect against myocardial injury after ischemia and reperfusion. Previous experiments from our laboratory using isolated, blood-perfused neonatal lamb and swine heart models have also shown that anti-CD18 [11] or anti-CD11b [12] antibody given before reperfusion improved ventricular functional recovery as well as recovery of vascular endothelial function [11]. Monoclonal antibodies directed against selectins have also been reported to prevent myocardial reperfusion injury. Weyrich and associates [13] demonstrated that monoclonal antibody that blocks P-selectin prevented leukocyte adherence to the coronary vasculature, reduced myocardial necrosis, and preserved endothelial function after normothermic ischemia and reperfusion. In experiments reported by Ma and colleagues [14], monoclonal antibodies against L-selectin had similar effects in a feline normothermic ischemia/reperfusion model.

A different approach to prevent leukocyte adhesion is the development of soluble substances that saturate the adhesion molecules expressed by activated neutrophils, platelets, or endothelial cells, thereby preventing their interaction with the appropriate ligands in the inflammatory process. One set of ligands for the selectins have been found to be specific carbohydrate-containing structures [5]. Sialyl Lewis X (SLe^x) oligosaccharides on the surface of leukocytes bind to P-selectin found on the surface of activated endothelium and activated platelets [3, 19]. The ligand for the L-selectin on leukocytes is thought to be a similar oligosaccharide, although it is not completely characterized [21]. Fucoidin is a sulfated fucosylated polysaccharide derived from seaweed that binds to both L- and P-selectin, and it has been found to block leukocyte rolling in a dose-dependent manner [5, 23]. The effects of fucoidin on leukocyte rolling over activated endothelium are present only while the fucoidin is circulating, and leukocytes can again adhere to activated endothelium when fucoidin is removed [23]. Previous in vitro studies have demonstrated that the function of both L-selectin and P-selectin were blocked by fucoidin, but it is unclear in the present experiments whether L- or P-selectin blockade may be more important. The studies by Ley and associates [23] using fucoidin in a model of chemical inflammation suggest that L-selectin blockade is more important. The 50% effective dose of fucoidin to block leukocyte rolling was 2.1 mg/L in the studies reported by Rochon and associates [24] and 2.5 mg/L in the studies reported by Ley and associates [23]. Kubes and colleagues [25] found that doses of 25 mg/kg body weight inhibited leukocyte rolling on postcapillary venules by 90% in a feline intestinal ischemia/reperfusion model. The 30 mg/L concentration we used in this experiment seems likely to have blocked the function of selectins, but did not cause obvious cardiac side effects. Experiments using an oligosaccharide analogue of SLe^x in normothermic ischemia/reperfusion models have shown reductions in myocardial injury and neutrophil accumulation in cats [26, 27] and dogs [28].

The approach of "saturation" blockade of adhesion molecules by ligand analogues may offer some advantages over anti-adhesive monoclonal antibody therapy. First, it seems possible to control the duration of the anti-adhesive effects using fucoidin as its effect is rapidly lost as fucoidin is cleared from the circulation. In contrast, monoclonal antibodies may need several minutes to bind to the specific antigen, and the effect may last for several hours until the binding between antibody and antigen ceases. Thus, it may be more difficult to control the duration of the effect of the antibody appropriately. Second, the potential problems of sensitization to monoclonal antibodies may be considerable, and this consideration becomes more important when multiple exposures may be necessary (as in patients having reoperations) or when "nonhumanized" antibodies are used. Finally, because leukocyte rolling on the endothelium is the initial step in the inflammatory process, there is some intuitive appeal to interrupting the inflammatory process at its earliest stages.

In summary, the present study demonstrates that selectin-mediated endothelial-leukocyte interactions may play an important role in myocardial ischemia and reperfusion that occurs under the hypothermic conditions frequently employed in clinical cardiac operations. Blockade of the selectins by fucoidin had beneficial effects on recovery of LV function and CBF after 2 hours of cold cardioplegic ischemia. Therapeutic use of this or similar anti-adhesion strategies may improve the recovery of myocardial and coronary vascular function after cardiac operations. Additional studies in the whole animal and with similar agents are underway.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We sincerely thank Mark A. Cioffi, MAT, for his technical assistance.

Supported by grant HL48675-05 from the National Institutes of Health.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Presented at the Thirty-second Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 29–31, 1996.

Address reprint requests to Dr Mayer, Department of Cardiovascular Surgery, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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