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J Thorac Cardiovasc Surg 1998;116:1060-1069
© 1998 Mosby, Inc.
CARDIOPULMONARY SUPPORT AND PHYSIOLOGY |
From the Division of Cardiothoracic Surgery (M.T., C.M., F.W.S.), Department of Surgery, Cardiovascular Division (M.S.), Department of Medicine, Beth Israel-Deaconess Medical Center, Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology (G.L.S., A.A.), Brigham and Women's Hospital, and Harvard Medical School, Boston, Mass.
Received for publication April 20, 1998. Revisions requested July 16, 1998.Revisions received July 28, 1998. Accepted for publication Aug 2, 1998. Address for reprints: Frank W. Sellke, MD, Division of Cardiothoracic Surgery Beth Israel-Deaconess Medical Center, East Campus, Dana 905, 330 Brookline Ave, Boston, MA 02215.
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1-5
The complement fragments C3a, C5a, and C5b-9 all gradually increase in concentration after the initiation of CPB and play a major role in mediating the systemic inflammatory response observed during and after CPB. C5a and C5b-9 may directly activate PMNs 6,7 and induce increased expression of the P-selectin and other adhesion molecules on endothelial cell sufaces. 8,9 Deposition of C5b-9 can be observed on endothelial cells soon after the initiation of reperfusion 10 and can directly attenuate endothelium-dependent relaxation. 11 In this regard, Rinder and associates 12 using an in vitro model, have recently reported that an anti-human C5 monoclonal antibody blocks cleavage of C5 and effectively attenuates leukocyte activation during CPB. However, specific inhibition of C5a has not been fully tested in a clinically relevant model of CPB and cardioplegia-reperfusion.
In this study, we assessed the efficacy of a monoclonal antibody to C5a in modulating neutrophil chemotaxis and aggregation and complement-mediated hemolysis. Then we used an in vivo porcine model of CPB and cardioplegia-reperfusion to determine the role of C5a-mediating coronary microvascular endothelial dysfunction, myocardial neutrophil infiltration, systemic complement activation, myocardial edema formation, and possible altered expression of the inducible (iNOS) and constitutive (cNOS) isoforms of nitric oxide synthase.
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Porcine PMN purification, chemotaxis, and aggregation studies
Porcine PMN aggregation and chemotaxis studies were performed as we have previously described. 13,14 Zymosan-activated porcine sera (PAS; 10 µL) was used as the chemotactic agent. GS1 (0 to 51 µg/mL) was added to the PAS for 30 minutes before application to the chemotaxis wells.Animal preparation. Yorkshire pigs (20 to 25 kg) of either sex were premedicated with ketamine (10 mg/kg, intramuscularly) and anesthetized with 
-chloralose and urethane (60 mg/kg and 300 mg/kg intravenously initially and then 15 mg/kg and 60 mg/kg every 60 minutes as needed, respectively). Pigs were intubated and mechanically ventilated (Harvard Apparatus Inc, South Natick, Mass). In the control group (n = 6), a sternotomy was performed, and the pigs were heparinized (500 units/kg). The hearts were rapidly excised and immediately placed in a cold (4°C to 10°C) Krebs buffer solution of the following composition (in millimolars): 118.3 NaCl, 4.7 KCl, 2.5 CaCl2, 1.2 MgSO4, 1.2 NaH2PO4, 25.0 NaHCO3, and 11.1 glucose.
In 12 pigs, after the induction of anesthesia and tracheal intubation, fluid-filled catheters were introduced into the femoral artery for the measurement of peripheral arterial pressure. After a sternotomy was performed, purse-string sutures were placed in the distal ascending aorta and the right atrium. Instantaneous left anterior descending coronary artery (LAD) blood flow was measured with a 2.5-mm ultrasonic transit-time flow probe (model 2.5S; Transonic System Inc, Ithaca, NY) that was placed around the LAD distal to the second diagonal branch. The flow probe was connected to a flow monitor (model T206; Transonic System Inc). A pair of ultrasonic crystals was implanted 10 to 15 mm apart and approximately 3 mm beneath the surface of the left ventricular subepicardium. The crystals were placed parallel to the long axis of the left ventricle. An 8F micromanometer-tipped catheter (model SPC-370; Millar Instruments, Houston, Tex) was placed in the left ventricle through the apex for the measurement of left ventricular systolic pressure (LVSP) and rate of change of LV pressure (LV dP/dt). LV dP/dt, the first derivative of LV pressure, was derived by differentiating the left ventricular pressure signal over time. Six pigs were randomized to receive anti-C5a monoclonal antibody (GS1; 1.6 mg/kg) intravenously 20 minutes before the onset of CPB. Six pigs received saline solution vehicle alone. Pigs were given heparin (500 units/kg) and cannulated via the distal ascending aorta and the right atrium through the purse-string sutures. Activated clotting time was maintained for more than 400 seconds. A left ventricular vent was placed via the left ventricular apex for decompression. A small cannula was inserted into the ascending aorta through another purse-string suture for the infusion of cardioplegic solution. Normothermic CPB was instituted with a bubble oxygenator (Bentley Bio-2; Baxter Healthcare Corp, Irvine, Calif) and a standard roller pump. An arterial filter (Bentley Bio-1025; Baxter Healthcare Corp) was inserted into the circuit distal to the roller pump. Blood flow was maintained from 2.0 to 3.0 L/min (2.6 to 4.2 L/min/m2) to maintain a mean perfusion pressure of 40 to 70 mm Hg. Systemic blood temperature was maintained at 37°C during the entire study. Arterial blood gases were obtained (model 1306, pH/Blood Gas Analyzer; Instrumentation Laboratory, Lexington, Mass) before CPB was begun and at approximately 15-minute intervals thereafter. Arterial blood gases were adjusted by ventilatory rate and tidal volume to maintain PaO2 more than 50 mm Hg, PCO2 more than 30 and less than 45 mm Hg, and pH between 7.30 and 7.45. After stabilization of the preparation for CPB, an aortic crossclamp was placed and 300 mL of a cold (0°C to 4°C) hyperkalemic crystalloid cardioplegic solution was infused into the aortic root at a pressure of 60 mm Hg. The composition of hyperkalemic crystalloid cardioplegic solution was (in millimoles per liter): 121 NaCl, 25 KCl, 12 NaHCO3, 11.1 glucose, in purified water. Saline solution slush was placed on the surface of the heart to provide topical hypothermia during the crossclamp period. Myocardial temperature in the distribution of LAD was measured with a probe and ranged from 4°C to 10°C during the ischemic period. Infusion of the cardioplegic solution (150 mL) was repeated at 20-minute intervals for 60 minutes (2 additional doses). The aortic crossclamp was removed after 60 minutes of cardioplegic arrest, and the heart was reperfused with normothermic blood from the bypass circuit. The heart was kept decompressed with a left ventricular vent until a stable rhythm was obtained. Attempts were made to maintain the mean reperfusion pressure between 40 and 70 mm Hg. In the event of ventricular fibrillation, lidocaine (10 mg) was infused intravenously, and the heart was defibrillated with 10 J after the myocardial temperature rose to greater than 30°C. Pigs were weaned from CPB and decannulated. Heparin was not reversed with protamine. After 120 minutes of reperfusion, the heart was rapidly excised and immediately placed in a cold Krebs buffer solution or in liquid nitrogen. All animals received humane care in compliance with the Beth Israel Deaconess Medical Center Animal Care and Use Committee and the National Research Council's "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animals and published by the National Institutes of Health (NIH Publication No. 86-23, revised 1985).
Hemodynamic measurements
The following parameters were measured every 30 minutes: LAD blood flow, mean peripheral arterial pressure (MAP), LVSP, LV maximum dP/dt (LV max dP/dt), and percent segmental shortening. Percent segmental shortening was calculated as follows: 100 x (end-diastolic segment length—end-systolic segment length)/end-diastolic segment length, where end-diastolic segment length was measured at the onset of LV dP/dt and end-systolic segment length was measured at peak negative LV dP/dt.
Measurement of GS1 antibody in porcine plasma
Murine antibody concentrations were measured in porcine plasma collected at various times during the course of the CPB procedure as described before with modifications. 15 Briefly, 50 µL of a polyclonal antibody to murine IgG (2 µg/mL in sodium carbonate buffer) was placed in each well of a 96-well microtiter plate and incubated overnight at 4°C. The plate was washed and blocked with 3% bovine serum albumin for 2 hours at room temperature. The plates were then washed, covered, and placed at –20°C until used for the ELISA. Known amounts of murine IgG antibody were used to generate a standard curve from 10 µg/mL to 1 ng/mL. Unknown pig plasma samples were diluted 1:40 with Hanks' balanced salt buffer and run in duplicate on the ELISA plates. After the plates were washed, a goat polyclonal anti-murine IgG antibody conjugated with horseradish peroxidase was added and incubated for 1 hour at room temperature. The plate was washed and then developed with 2,2´azino-bis(3-ethylbenzthiol) sulfonic acid and read on a plate reader (Molecular Devices, Sunnyvale, Calif).
Microvascular preparation
Arterial microvessels (60 to 180 µm, internal diameter) were dissected from the LAD-dependent subepicardial region in the left ventricle (stored in cold Krebs buffer) with a x10 to x60 dissecting microscope (Olympus Optical, Tokyo, Japan) within 6 hours of completion of the animal experiment. Microvessels were placed in a microvessel chamber (University of Iowa Medical Instrumentation, Iowa City, Iowa), cannulated with dual glass micropipettes measuring 40 to 80 µm in diameter, and secured with 10-0 nylon monofilament suture (Ethicon, Inc, Somerville, NJ). Oxygenated (95% oxygen/5% carbon dioxide) Krebs buffer solution warmed to 37°C was continuously circulated through the organ chamber. The vessels were pressurized to 40 mm Hg in a no-flow state with a burette manometer filled with a Krebs buffer solution. With an inverted microscope (x40 to x200, Olympus CK2; Olympus Optical) connected to a video camera, the vessel image was projected onto a black-and-white television monitor. An electronic dimension analyzer (Living System Instrumentation, Burlington, Vt) was used to measure internal lumen diameter. Measurements were recorded (Graphtec, Irvine, Calif). Vessels were allowed to bathe in the organ chamber for at least 30 minutes before an intervention.
Microvessel study protocols
In all experimental groups, relaxation responses of microvessels were examined after precontraction of coronary microvessels with acetylcholine chloride by 20% to 70%. Once the steady-state tone was reached, the dose responses of the coronary microvessels to adenosine 5´-diphosphate (ADP; receptor-mediated endothelium-dependent vasodilators 10–9to 10–4 mol/L) and clonidine hydrochloride (2-adrenoceptor agonist, 10–9 to 10–5 mol/L), and the endothelium-independent vasodilators sodium nitroprusside (endothelium-independent vasodilator, 10–9 to 10–4 mol/L) and isoproterenol (ß-adrenoceptor agonist, 10–12 to 10–6 mol/L) were examined. Measurements were made and recorded 2 to 3 minutes after the drug was administered, when the response had stabilized. All drugs were applied extraluminally. One to 4 interventions were performed on each vessel. The order of the drug administration was random. The vessels were washed with a Krebs buffer solution and allowed to equilibrate in a drug-free Krebs buffer solution for 15 to 30 minutes between interventions.
Amplification and quantitation of cNOS and iNOS cDNA fragment by reverse transcriptase–polymerase chain reaction
To examine myocardial mRNA of the cNOS and the iNOS, reverse transcriptase–polymerase chain reaction (RT-PCR) was performed. cNOS and iNOS fragments were amplified by RT-PCR from myocardium stored in liquid nitrogen. Primers were designed based on the published cNOS 16 and iNOS sequence. 17 The primers of the sense 5´-AGACCCCTGGAAAGGGAG-3´ corresponding to bases 1443-1460 and the antisense 5´-TGTGTTACTGGATTCCTTCC-3´ corresponding to bases 1901-1920 were used to amplify a 486–base pair fragment of cNOS. 16 For iNOS, the primer of sense 5´-GCCTCGCTCTGGAAAGA-3´ corresponding to bases 1425-1441 and the antisense 5´-TCCATGCAGACAACCTT-3´ corresponding to bases 1908-1924 were used to amplify a 500–base pair fragment of cNOS. 17 An equal amount of total RNA was used for RT-PCR from control and experimental groups. For quantification, glyceraldehyde-3-phosphate dehydrogenase was amplified from the same amount of RNA to correct for variation of different samples. The PCR products were loaded in 1.5% agarose gel, scanned, and measured on an Image-Quant software (Molecular Dynamics, Sunnyvale, Calif).
Myocardial myeloperoxidase activity
Tissue samples from the left ventricle were excised at the end of reperfusion, frozen in liquid nitrogen, and stored at –80°C until assayed. Myeloperoxidase activity was measured as Amsterdam and associates 18 previously described. Ice-cold, minced sections of the tissues were homogenized (10% wt/vol) with a Polytron homogenizer (Brinkmann Instruments, Westbury, NY) in 50 mmol/L phosphate buffer solution (pH 6.0) containing 0.5% hexadecyltrimethyl-ammonium bromide for 15 seconds twice. The homogenates were then sonicated for 15 seconds, and the supernatant containing the myeloperoxidase enzyme was separated from the cellular debris by centrifugation at 20,000g for 15 minutes (2°C). The appearance of a colored product from the myeloperoxidase-dependent reaction of o-dianisidine and hydrogen peroxide (0.0005%) was spectrophotometrically detected with 100 mL of supernatant, 1.9 mL of hydrogen peroxide, and o-dianisidine in 50 mmol/L phosphate buffer solution (pH = 6.0). Supernatant myeloperoxidase activity was kinetically quantified on a temperature-controlled (25°C) spectrophotometer. The absorbance at 460 nm was recorded for several minutes, and the change in absorbance over 1 minute was measured during the linear portion (0.5 to 1.5 minute) of the tracing. One unit of myeloperoxidase activity was defined as that which degraded 1 mol hydrogen peroxide/minute at 25°C. Assessment of this assay with isolated porcine neutrophils demonstrated a linear relationship (r = 0.92) between myeloperoxidase and the number of cells, such that 1 unit of myeloperoxidase activity correlated with 2.9 x 106 neutrophils.
Porcine sera induced hemolytic assay
Sheep red blood cells were sensitized by standard methods, as described. 14 Sera dilutions of porcine sera were treated with GS1 (5 or 17 µg/mL).
Percent tissue water
The left ventricular tissues were weighed, incubated at 110°C for 12 hours, and then weighed again. Percent tissue water was calculated as follows: (wet weight – dry weight)/wet weight x 100.
Drugs
Isoproterenol, acetylcholine chloride, adenosine 5´-diphosphate, and sodium nitroprusside were obtained from Sigma Chemical Company (St Louis, Mo). Clonidine hydrochloride was obtained from Research Biomedicals International (Natick, Mass). All drugs were dissolved in ultrapure distilled water and prepared on the day of the study. Other reagents were obtained from the source listed in the text.
Statistical analysis
Data in the text and tables are presented as mean ± SD. The relaxation responses in the figures are expressed as the percent relaxation of the acetylcholine precontracted diameter (mean ± SEM) of the microvessels. Comparisons of dose-response curves of all experimental groups were performed by 2-way analysis of variance with repeated measure design followed by Scheffe's multiple comparison test when indicated. Comparison of hemodynamic variables, myeloperoxidase activities, myocardial wet/dry ratios, and gene expressions were compared with 1-way ANOVA and Scheffe's test post hoc with Statview 4.02 (Abacus Concepts, Inc, Berkeley, Calif). PMN GS1 antibody effects were compared with 1-way ANOVA and Neuman-Keuls test post hoc with Sigma Stat 2.0 (Jandel Scientific Software, SPSS, Inc, Chicago, Ill).
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Endothelium-dependent relaxation
Relaxation responses to the receptor-mediated endothelium-dependent vasodilator ADP were significantly reduced in the saline solution group (P = .01 vs control; Fig. 5). The responses to ADP were preserved in the GS1 group (P = .01 vs saline solution group). Similarly, relaxation responses to the 2-adrenoceptor agonist and endothelium-dependent vasodilator clonidine were significantly reduced after cardioplegia-reperfusion (P = .01 vs control; Fig. 6). Relaxation to clonidine was preserved in pigs treated with the GS1 antibody.
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cNOS and iNOS expression
The expressions of cNOS in the saline solution group (0.32 ± 0.13, cNOS signal density/glyceraldehyde-3-phosphate dehydrogenase density; P > .2) or the GS1 group (0.58 ± 0.68, P > .2) were unchanged in the myocardium after cardioplegia and reperfusion compared with that in control myocardial specimens (0.21 ± 0.16). However, iNOS expression was increased 2-fold after cardioplegia and 2 hours of reperfusion in the saline solution group (1.03 ± 0.50; P = .03) compared with that in the control myocardium (0.41 ± 0.17). The increased expression of iNOS in the GS1 group (0.93 ± 0.91; P > .2 vs control) was not statistically significant. There was no effect of GS1 antibody on the expression of either isoform of NOS. Representative blots are shown in Fig. 9.
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Wet/dry ratio
Myocardial wet/dry ratio was 4.21 ± 0.17 in the control group, and 4.68 ± 0.34 (P = .03 vs control) and 4.69 ± 0.24 (P = .03 vs control) in the saline solution and GS1 groups, respectively. Although a significant increase in myocardial water was noted between the control and saline solution groups, GS1 did not reduce the ratio.
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13-15,18,19 However, pure ischemia and ischemia under conditions of myocardial protection and CPB may produce different cellular and biochemical injury. It is known the complement activation is involved in alterations of vascular and myocardial function after ischemia or CPB. 5,10,14,20 The terminal membrane attack complex C5b-9 has a direct cytolytic action, 11,21 whereas the complement anaphylatoxin C5a has indirect actions including increased PMN activation, chemotaxis, aggregation, and vascular plugging. 22,23 This may, in theory, lead to increased vascular permeability and altered endothelial function.
Endothelium-dependent relaxation of coronary microvessels to ADP and clonidine was significantly improved with C5a inhibition in this model of cardioplegia-reperfusion. The associated reduction of myeloperoxidase activity suggests that the reduced PMN chemotaxis and adhesion leads to the benefical effect on vasomotor regulation and NOS activity. Because complement activation was not inhibited by the administration of GS1 (no change in CH50), the cytolytic and other actions of the C5b-9 terminal membrane attack complex may not be the only causes of endothelial dysfunction after CPB and cardioplegia, although C5b-9 certainly plays a role. During myocardial ischemia, subcellular membrane fragments activate the complement cascade 24 that play an important role in mediating reperfusion injury. Immediately after the onset of myocardial reperfusion, the alternative complement pathway is activated. 18 Unlike pure myocardial ischemia or cardioplegia, CPB itself activates the alternate complement pathway. In addition, the formation of the protamine-heparin complex formation shortly after administration of protamine potently activates the classic complement pathway. 25 Thus multiple factors lead to activation of the complement cascades during CPB and cardioplegia, including tissue ischemia, contact of blood with foreign surfaces, and pharmacologic agents. Surprisingly, myocardial function after reperfusion in our study was not improved with administration of the GS1, as has been reported in a myocardial infarction model using a similar monoclonal antibody to C5a. 18 This may be due to a difference between our clinically applicable model of cardioplegia and other models of ischemia-reperfusion that do not include CPB or cardioplegia. On the other hand, these findings may suggest that the endothelium of the coronary microvasculature is more sensitive to the effects of C5a than is myocardial contractile function. However, it is also possible that a longer duration of cardioplegia or reperfusion may have brought out a beneficial functional effect of C5a inhibition. One potential criticism of the study is that the GS1 antibody may not have been effective in inhibiting the effects of C5a. However, the concentration of the GS1 used in the study clearly was sufficient to inhibit the effects of C5a on PMN chemotaxis and aggregation. Furthermore, GS1 reduced neutrophil infiltation in the myocardium and improved endothelial function. Thus lack of efficacy of the antibody was ruled out as a cause for the failure of GS1 to improve myocardial recovery after cardioplegia.
Because improvement of myocardial contractile function after reperfusion was not observed, selective inhibition of C5a did improve the impaired endothelium-dependent relaxation via release of nitric oxide from the microvascular endothelium that has been reported previously. 26 One factor potentially contributing to this may be an alteration in the expression of cNOS, through which ADP and clonidine cause the release of nitric oxide. Increased concentration of circulating cytokines during CPB and cardioplegia may lead to an increased expression of iNOS, which has been implicated in causing cellular injury through direct actions or indirectly via formation of the peroxynitrite free radical. In this study, expression of iNOS was slightly increased after 1 hour of cardioplegia and 2 hours of reperfusion. It is probable that prolonged reperfusion would lead to greater iNOS expression because the altered expression of the iNOS gene has been reported to require 4 or more hours in many studies. On the other hand, the expression of cNOS was not altered after cardioplegia, nor was the cNOS expression affected by the GS1 antibody. Thus altered expression of either isoform of NOS did not contribute to improvement in endothelium-dependent relaxation or to the reduced infiltration of PMNs in the myocardium as a result of GS1 administration.
In summary, a selective inhibition of complement fragment C5a limits PMN-mediated impairment of endothelium-dependent relaxation after CPB and cardioplegia-reperfusion. Therefore the modulation of complement has the potential to improve the recovery of patients after cardiac operation, because of decreased vascular permeability, improved vasomotor regulation, and maintenance of the activity of NOS and other homeostatic mechanisms. 27 However, despite clear inhibition of myocardial PMN infiltration and preservation of endothelial function, GS1 had no effect on short-term myocardial functional improvement.
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2-plasmin-inhibitor complexes during cardiopulmonary bypass. Blood 1989;73:468-71. This article has been cited by other articles:
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  N. C. Riedemann and P. A. Ward Complement in Ischemia Reperfusion Injury Am. J. Pathol., February 1, 2003; 162(2): 363 - 367. [Full Text] [PDF]
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 H. Zhao, M. C. Montalto, K. J. Pfeiffer, L. Hao, and G. L. Stahl Murine model of gastrointestinal ischemia associated with complement-dependent injury J Appl Physiol, July 1, 2002; 93(1): 338 - 345. [Abstract] [Full Text] [PDF]
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 D. Paparella, T.M. Yau, and E. Young Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update Eur. J. Cardiothorac. Surg., February 1, 2002; 21(2): 232 - 244. [Abstract] [Full Text] [PDF]
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 G. A. Kalweit, J. D. Schipke, E. Godehardt, and E. Gams Changes in coronary vessel resistance during postischemic reperfusion and effectiveness of nitroglycerin J. Thorac. Cardiovasc. Surg., November 1, 2001; 122(5): 1011 - 1018. [Abstract] [Full Text] [PDF]
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E. G. Araujo, C. Bianchi, K. Sato, R. Faro, X. A. Li, and F. W. Sellke Inactivation of the MEK/ERK pathway in the myocardium during cardiopulmonary bypass J. Thorac. Cardiovasc. Surg., April 1, 2001; 121(4): 773 - 781. [Abstract] [Full Text] [PDF]
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 M. C. Montalto, C. D. Collard, J. A. Buras, W. R. Reenstra, R. McClaine, D. R. Gies, R. P. Rother, and G. L. Stahl A Keratin Peptide Inhibits Mannose-Binding Lectin J. Immunol., March 15, 2001; 166(6): 4148 - 4153. [Abstract] [Full Text] [PDF]
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R. D. Riley, H. Sato, Z.-Q. Zhao, V. H. Thourani, J. E. Jordan, A. X. Fernandez, X.-L. Ma, D. R. Hite, D. F. Rigel, T. C. Pellas, et al. Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization J. Thorac. Cardiovasc. Surg., August 1, 2000; 120(2): 350 - 358. [Abstract] [Full Text] [PDF]
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A. Agah, M. C. Montalto, C. L. Kiesecker, M. Morrissey, M. Grover, K. L. Whoolery, R. P. Rother, and G. L. Stahl Isolation, Characterization, and Cloning of Porcine Complement Component C7 J. Immunol., July 15, 2000; 165(2): 1059 - 1065. [Abstract] [Full Text] [PDF]
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C. D. Collard, A. Vakeva, M. A. Morrissey, A. Agah, S. A. Rollins, W. R. Reenstra, J. A. Buras, S. Meri, and G. L. Stahl Complement Activation after Oxidative Stress : Role of the Lectin Complement Pathway Am. J. Pathol., May 1, 2000; 156(5): 1549 - 1556. [Abstract] [Full Text] [PDF]
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 M. Tofukuji, G. L. Stahl, C. Metais, M. Tomita, A. Agah, C. Bianchi, M. P. Fink, and F. W. Sellke Mesenteric dysfunction after cardiopulmonary bypass: role of complement C5a Ann. Thorac. Surg., March 1, 2000; 69(3): 799 - 807. [Abstract] [Full Text] [PDF]
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 C. D. Collard, A. Agah, W. Reenstra, J. Buras, and G. L. Stahl Endothelial Nuclear Factor-{kappa}B Translocation and Vascular Cell Adhesion Molecule-1 Induction by Complement : Inhibition With Anti-Human C5 Therapy or cGMP Analogues Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2623 - 2629. [Abstract] [Full Text] [PDF]
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 J. E. Jordan, Z.-Q. Zhao, and J. Vinten-Johansen The role of neutrophils in myocardial ischemia-reperfusion injury Cardiovasc Res, September 1, 1999; 43(4): 860 - 878. [Abstract] [Full Text] [PDF]
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 K. W. Park, M. Tofukuji, C. Metais, M. E. Comunale, H. B. Dai, M. Simons, G. L. Stahl, A. Agah, and F. W. Sellke Attenuation of Endothelium-Dependent Dilation of Pig Pulmonary Arterioles After Cardiopulmonary Bypass Is Prevented by Monoclonal Antibody to Complement C5a Anesth. Analg., July 1, 1999; 89(1): 42 - 42. [Abstract] [Full Text] [PDF]
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 J. Szebeni, J. L. Fontana, N. M. Wassef, P. D. Mongan, D. S. Morse, D. E. Dobbins, G. L. Stahl, R. Bunger, and C. R. Alving Hemodynamic Changes Induced by Liposomes and Liposome-Encapsulated Hemoglobin in Pigs : A Model for Pseudoallergic Cardiopulmonary Reactions to Liposomes: Role of Complement and Inhibition by Soluble CR1 and Anti-C5a Antibody Circulation, May 4, 1999; 99(17): 2302 - 2309. [Abstract] [Full Text] [PDF]
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