(Stroke. 1995;26:1438-1443.)
© 1995 American Heart Association, Inc.
Articles |
Anti–Intercellular Adhesion Molecule–1 Antibody Reduces Ischemic Cell Damage After Transient But Not Permanent Middle Cerebral Artery Occlusion in the Wistar Rat
From the Henry Ford Health Sciences Center, Department of Neurology, Detroit, Mich (R.L.Z., M.C., N.J., J.P.); Oakland University, Rochester, Minn (M.C., W.X.T.); and the Upjohn Company, Department of Adhesion Biology, Kalamazoo, Mich (A.M.M., D.C.A.).
Correspondence to Michael Chopp, PhD, Neurology Department, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202.
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Abstract |
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Background and Purpose Postischemic cerebral inflammation may contribute to ischemic cell damage. Intercellular adhesion molecule–1 (ICAM-1) is a glycoprotein expressed on endothelial cells that facilitates leukocyte adhesion. We investigated the effect of administration of an anti–ICAM-1 antibody (1A29) on ischemic cell damage after transient (2-hour) or permanent middle cerebral artery (MCA) occlusion in the Wistar rat.
Methods Groups studied were as follows: (1) transient MCA occlusion: rats were subjected to 2 hours of MCA occlusion, and after 1 hour of reperfusion they were treated with 1A29 (n=11) or an isotype control antibody (n=9); and (2) permanent MCA occlusion: rats were treated with 1A29 (n=9) or an isotype control antibody (n=7) 2 hours after onset of MCA occlusion. All animals were killed 1 week after onset of ischemia. Brain sections were stained with hematoxylin and eosin for histological evaluation.
Results Significant reductions (P<.05) in both volume (44%) of the ischemic lesion and weight loss were found in animals subjected to transient MCA occlusion and treated with 1A29 compared with vehicle-treated animals. In contrast, in animals subjected to permanent MCA occlusion the lesion and the temporal profile of body weight were not altered by 1A29 administration.
Conclusions Ischemic cell damage is promoted by postischemic inflammatory response after 2 hours of transient MCA occlusion, and ischemic cell damage is reduced by administration of an anti–ICAM-1 antibody during reperfusion.
Key Words: cerebral ischemia, focal • leukocytes • middle cerebral artery • rats
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ischemic cell damage after MCA occlusion may be mediated by many factors, among which are inflammatory processes.1 2 3 4 The migration of leukocytes into injured tissue is regulated in part by specific cell-surface integrins, the CD18 receptor complex.5 6 7 ICAM-1 is a cell surface glycoprotein that is expressed on vascular endothelium and other cells.8 ICAM-1 expression facilitates leukocyte adhesion to endothelium and is a ligand for the CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1) integrins that are expressed in the leukocyte.9 10 11
Treatment with the anti–ICAM-1 antibody reduces neurological deficits after spinal cord injury and embolic stroke in the rabbit.12 13 We recently tested the effect of an anti–ICAM-1 antibody on ischemic cell damage. Rats were administered anti–ICAM-1 antibody immediately upon reperfusion after 2 hours of MCA occlusion, and the animals were killed 2 days after onset of reperfusion.14 A significant reduction in the volume of the lesion (44%, P<.05) concomitant with reduction of neutrophils in the ischemic tissue and an improved physiological function were present when the anti–ICAM-1 antibody was administered immediately upon reperfusion. Thus, these data support the hypothesis that neutrophils contribute to ischemic cell damage and blocking of ICAM-1 expression reduces ischemic cell damage. We now extend our previous study to address several questions relevant to the development of the anti–ICAM-1 therapeutic intervention: (1) Does the anti–ICAM-1 intervention reduce ischemic cell damage when administered after 1 hour of reperfusion (3 hours after onset of ischemia)? Clearly, the longer we delay administration of a therapeutic intervention the more relevant it becomes to the clinical environment. (2) Does anti–ICAM-1 intervention reduce ischemic cell damage when administered to animals subjected to permanent MCA occlusion? Is reperfusion a necessary condition to derive benefit from this therapy? (3) In our previous study animals were killed 2 days after the onset of ischemia. We therefore test the hypothesis that the beneficial effect of the anti–ICAM-1 intervention persists at least 1 week after onset of ischemia. Thus, it is likely that this intervention does not simply delay the maturation of the lesion but may provide prolonged benefit.
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Materials and Methods |
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All surgical procedures and experiments were performed with the approval of the Care of Experimental Animals Committee at Henry Ford Hospital.
Male Wistar rats (weight, 270 to 290 g; n=36) were used in the experiments. MCA occlusion was induced by advancing a 4-0 surgical nylon filament into the internal carotid artery to block the origin of the MCA.2 15 Briefly, animals were anesthetized with 3.5% halothane, and anesthesia was maintained with 0.5% to 1.0% halothane in 70% N2O and 30% O2 with the use of a face mask. Rectal temperature was maintained at 37°C throughout the surgical procedure with the use of a feedback-regulated water heating system. The right femoral artery and vein were cannulated for measuring blood gases (pH, PO2, PCO2) before ischemia, monitoring blood pressure during the surgery, and administering drugs. A length of 18.5- to 19.0-mm 4-0 surgical nylon filament with its tip rounded by heating near a flame was advanced from the external carotid artery into the lumen of the internal carotid artery until it blocked the origin of the MCA. In the transient MCA occlusion experiment, 2 hours after MCA occlusion animals were reanesthetized with halothane, and reperfusion was performed by withdrawal of the filament until the tip became visible at the origin of the lumen of the external carotid artery. In the permanent MCA occlusion study, the nylon filament remained in place until the animals were killed. Ischemic animals were weighed before ischemia and daily after onset of ischemia.
Animals were randomly divided into four groups. (1) In the transient ischemia anti–ICAM-1 group (n=11), rats were subjected to MCA occlusion, and 1A29 was infused over a 3-minute interval at a dose of 2 mg/kg IV at 1 hour after reperfusion and 1 mg/kg IV at 22 hours after reperfusion. (2) In the transient ischemia control group (n=9), rats were subjected to MCA occlusion, and an isotype-matched control antibody (mouse IgG1, Sigma) was administered at 1 hour and 22 hours of reperfusion, with the same volume dose as the 1A29 group. The control antibody has an endotoxin level of less than 1.0 eu/mg. (3) In the permanent ischemia group (n=9), rats were subjected to MCA occlusion, and 1A29 was infused over a 3-minute interval at a dose of 2 mg/kg IV at 2 hours after onset of occlusion and 1 mg/kg IV at 24 hours after ischemia. (4) In the permanent ischemia control group (n=7), rats were subjected to MCA occlusion, and an isotype-matched control antibody was administered at 2 hours and 24 hours of occlusion, with the same volume dose as used in the 1A29 group. An additional 9 rats without ischemia were used to measure the peripheral blood leukocytes after 1A29 or control antibody infusion. Animals were administered 1A29 (n=6) or control antibody (n=3) at a dose of 2 mg/kg IV at 0 hours and 1 mg/kg IV at 22 hours after the first infusion. Peripheral blood samples were obtained before the first infusion and after 15 minutes and 2, 4, 24, 48, 72, 96, 120, 144, and 168 hours. Measurements of peripheral WBC counts and differentials were performed manually with the use of a hemocytometer and by blood smears stained with Wright-Giemsa, respectively. One hundred cells were counted for each of the differentials. The percentage of differentials was multiplied by the WBC counts to obtain the absolute number per milliliter of blood.
Antibody to rat ICAM-1, designated 1A29,16 reacts with 85- to 89-kD epitope present on cytokine-activated rat endothelial cells. The antibody recognizes rat ICAM-1 (based on its ability to inhibit homotypic aggregation of T-cell blasts induced by phytohemagglutinin), by analysis in sodium dodecyl sulfate–polyacrylamide gel electrophoresis of the antigen precipitated by antigen distribution on frozen sections of postcapillary high endothelial venules, and by cytokine-induced upregulation of the antigen on rat endothelial cells.16 The endotoxin level of the anti–ICAM-1 antibody is less than 0.35 eu/mg. In addition, the 1A29 specifically recognizes Chinese hamster ovary cells transfected with rat ICAM-1 cDNA.17
Animals were anesthetized with ketamine (44 mg/kg IM) and xylazine (13 mg/kg IM) at 1 week after onset of ischemia. Rats were transcardially perfused with heparinized saline and 10% buffered formalin, and brains were removed. Each brain was cut into 2-mm-thick coronal blocks, for a total of seven blocks per animal, with the use of a rat brain matrix. The brain tissue was processed and embedded, and 6-µm-thick paraffin sections from each block were cut and stained with hematoxylin and eosin for histopathological evaluation.
Tissue volume was measured blindly with the use of a GLOBAL LAB IMAGE analysis program (Data Translation). Each hematoxylin and eosin section was evaluated at x2.5 magnification. In each coronal section, the area of infarct and the ipsilateral and contralateral hemispheric area (in square millimeters) were calculated by tracing the right and left hemispheres and the ischemic lesion on the computer screen, and the volumes (in cubic millimeters) were determined by multiplying the appropriate area by the section interval thickness.18 The indirect method for calculating infarct volume, in which the intact area of the ipsilateral hemisphere was subtracted from the area of the contralateral hemisphere, was used.19 20 The infarct volume is presented as the percentage of infarct lesion of the contralateral hemisphere.
One-way ANOVA followed by Bonferroni corrected t tests were performed to detect differences of ischemic infarct area within each coronal section and the volume of the ischemic lesion between the two groups. The Wilcoxon rank sum test was performed on the lesion area in each section between two groups. To detect differences in values between preantibody and postantibody administration or ischemia within each group, paired t tests were performed on the peripheral WBC and differential counts in the groups treated with antibody administration only and on the animal weights in the four groups that underwent MCA occlusion. All measurements were performed blindly (by R.L.Z., J.P., and W.X.T.). All data are presented as mean±SE.
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Results |
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Blood gases were within the normal physiological range in all four groups of animals. Blood pressure was stable during the infusion of antibodies (data not shown).
Table 1
shows the peripheral WBC and
differential counts in the 1A29 groups and the groups treated with
control antibody infusion only. No difference was detected in WBC and
differential values after antibody administration in both groups
compared with preantibody administration values.
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The percent infarct volume was significantly decreased in the
1A29-treated group after the transient ischemic insult compared
with the respective vehicle control group (Table 2). Fig 1 shows the area of infarction in each of the seven
coronal sections for both 1A29 antibody–treated and vehicle control
groups in animals subjected to transient and permanent MCA occlusion.
The area of infarction was reduced in sections 1, 2, 3, and 4 in the
1A29-treated group compared with the vehicle-treated group in animals
subjected to transient MCA occlusion (Fig 1, top panel), and
statistically significant differences were detected in sections 1, 2,
and 3 (P<.05).
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) (n=9) rats in the transient middle cerebral artery (MCA)
occlusion group (top) and in antibody-treated (+) (n=9) and
vehicle-treated (
In animals subjected to permanent MCA occlusion, no beneficial effect
of reducing percent volume of infarct was found in the 1A29-treated
animals compared with vehicle-treated animals (Table 2
and Fig 1,
bottom panel).
Fig 2 shows the animal body weight before and daily
after onset of MCA occlusion. 1A29-treated animals exhibited a
significant reduction of weight loss after transient ischemia
compared with vehicle-treated animals (Fig 2, top panel). In animals
subjected to permanent MCA occlusion, no difference in the temporal
profiles of body weight was detected between 1A29- and vehicle-treated
groups (Fig 2, bottom panel).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our data indicate that an intravenous administration of an anti–ICAM-1 antibody (1A29) at 1 hour of reperfusion after 2 hours of MCA occlusion significantly reduces the volume of infarct and lessens postischemic body weight loss in animals surviving for 7 days. In contrast, no protection was found in animals subjected to permanent MCA occlusion after the identical treatment protocol.
There are a number of possibilities as to why administration of anti–ICAM-1 antibody reduces ischemic cell damage after transient but not after permanent MCA occlusion in the rat. Permanent ischemia as a severe insult may simply overwhelm and nullify any beneficial effect derived from the anti–adhesion molecule therapy. A second possibility is that reperfusion may be a necessary condition for the activation of an inflammatory mechanism contributing to ischemic cell damage. Oxidative damage caused by reperfusion may be required to activate the upregulation of cytokines, chemokines, and adhesion molecules in a timely fashion, which allows these molecules to mediate the inflammatory response that provokes cell damage.21 22 The time course of neutrophil influx into ischemic tissue after MCA occlusion in the rat is also different for transient and permanent MCA occlusion.23 Transient MCA occlusion results in an earlier (by 1 day) peak influx of leukocytes into the ischemic tissue than does permanent ischemia. Thus, after permanent ischemia the inflammatory response may be delayed beyond the time at which it can evoke ischemic cell damage. The beneficial effect of anti–ICAM-1 administration after transient but not after permanent MCA occlusion suggests that this therapeutic intervention should be used in conjunction with thrombolysis, both because it is only effective after transient MCA occlusion and because transient MCA occlusion may predispose tissue to inflammatory-mediated damage.
Our data support the hypothesis that the appearance of leukocytes in injured ischemic tissue is not only a pathophysiological response to existing injury but also may promote ischemic injury.11 13 24 25 Acute leukocyte microvascular occlusion and leukocyte infiltration into ischemic tissue potentiate ischemic cell damage.26 27 28 Reduction of ischemic injury in the central nervous system of the rabbit after administration of anti–ICAM-1 antibody has been attributed to improved blood flow resulting from reduction of leukocyte endothelial adhesion.13 After transient MCA occlusion, we observed a significant reduction infarct size in antibody-treated animals compared with vehicle-treated animals. We have demonstrated that the reduction of infarct volume by anti–ICAM-1 treatment was associated with decreased activity of myeloperoxidase, indicating a reduction of neutrophil presence in infarcted tissue,14 and therefore we did not assess the myeloperoxidase activities in the present study. Our present data also indicate that 1A29 does not cause a reduction of peripheral neutrophils beyond the normal physiological range, implying that the protective effect of 1A29 against reperfusion ischemic injury is attributed to the blockage of leukocyte adhesion and transendothelial migration.13
We have not found a protective effect of the anti–ICAM-1 antibody on ischemic cell damage when used in a model of permanent MCA occlusion. Clark et al13 have also reported that administration of an anti–ICAM-1 antibody reduced central nervous systemic injury in the reversible spinal cord ischemia model but not in the irreversible brain ischemia model in rabbit. The difference in therapeutic efficacy between transient and permanent ischemia may provide a clue to the mechanisms of leukocyte-mediated injury. One of the proposed mechanisms of leukocyte potentiation of ischemia is microvascular occlusion caused by direct mechanical obstruction and the cytotoxic effects of leukocytes on the endothelium. When leukocytes are activated during ischemia, an orchestrated sequence of upregulation of both leukocyte and endothelial adhesion molecules occurs, which causes adhesion of the leukocyte to the capillary endothelium,29 leading to obstruction of the microcirculation. This capillary plugging may cause the "no-reflow" phenomenon.24 Areas of parenchyma that might be viable when blood flow returns are not adequately reperfused and ultimately die. Leukocyte granule contents also induce endothelial permeability, interstitial edema, and a further increase of leukocyte adhesion,30 exacerbating the low-flow state.27 Thus, treatment with anti–ICAM-1 antibody may reduce injury by improving blood flow during reperfusion.13 Neutrophils adhering to the endothelium may also damage the endothelium and increase the permeability of the blood-brain barrier.27 28 This leads to edema and a vicious cycle of ischemia and inflammatory response. Activated or adhering neutrophils may release free radicals, proteases, and toxic oxidative metabolites that initiate a cascade of damage.26 Given that the time course of neutrophil migration from the intravascular space into the parenchyma occurs over many hours (>4 hours) and that neutrophils are significantly increased in the ischemic tissue after hours of reperfusion,23 it is reasonable that the primary mechanism of neutrophil-mediated damage occurs when the neutrophil is within the microvasculature and that neutrophils promote ischemic cell damage by reducing cerebral blood flow, damaging the blood-brain barrier, or igniting the perpetuating process of oxidative burst.
The present data are consistent with and extend our previous findings that administration of a monoclonal antibody against ICAM-1 reduces ischemic damage when administered to animals subjected to 2 hours of MCA occlusion and 2 days of survival.14 From the previous study we cannot exclude the possibility that animals killed at time points beyond 48 hours after onset of MCA occlusion may not exhibit a permanent reduction of the lesion from 1A29 treatment. It is possible that administration of the anti–ICAM-1 antibody may simply delay the maturation of the ischemic lesion. The minimum time required for an infarct to become mature without any therapeutic intervention in this rat ischemia model is 2 to 3 days after onset of ischemia,23 31 32 and the therapeutic intervention may only delay progression of infarction, as has been demonstrated after hypothermic intervention,33 but not reduce ultimate infarct size. The present study, in which we killed the rats 7 days after onset of ischemia, at a time when an ischemic lesion progresses to infarction, supports a long-term benefit of anti–ICAM-1 therapeutic intervention.
An important finding is that the anti–ICAM-1 antibody is effective in reducing ischemic cell damage when administered during the reperfusion period, 3 hours after the initiation of ischemia. This has positive implications for application of this form of therapeutic intervention in the clinical environment, which demands a delayed intervention. The ability of anti–ICAM-1 therapy to be beneficial when instituted in the reperfusion period is consistent with its mode of operation in reducing postischemic inflammatory response. Further studies must be performed to test the latest time point after reperfusion at which this therapy can be applied. In addition, studies are required to identify the duration of ischemia for which this type of intervention is beneficial.
Our data on the reduction of ischemic cell damage after administration of anti–ICAM-1 antibody mirror our previous findings of a protective effect with anti-CD11b antibody.32 We have previously investigated the role of adhesion molecules expressed on the leukocytes in reducing ischemic cell damage.20 31 32 Thus, there appear to be symmetrical findings between anti–adhesion molecule antibodies expressed on the leukocyte and molecules expressed on the endothelial cell. These complementary data support the role of leukocytes in contributing to ischemic cell damage. Recent data suggest that combinations of antibodies against adhesion molecules may provide a synergistic beneficial reduction of ischemic cell damage, and testing this hypothesis in MCA models is therefore warranted.23
In conclusion, the administration of the anti–ICAM-1 antibody significantly reduced ischemic injury during reperfusion after transient but not after permanent MCA occlusion. Thus, inhibition of neutrophil adhesion may be useful in treating the brain after transient MCA occlusion.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by National Institute of Neurological Disorders and Stroke grants PO1-NS23393 and RO1-NS29463. The authors wish to thank Denice Janus for manuscript preparation and Qing Wang for technical assistance.
Received August 30, 1994; revision received March 24, 1995; accepted April 20, 1995.
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References |
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1. Barone FC, Schmidt DB, Hillegass LM, Price WJ, White RF, Feuerstein GZ, Clark RK, Lee EV. Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke. 1992;23:1337-1348.
2. Chen H, Chopp M, Zhang ZG, Garcia JH. The effect of hypothermia on the transient cerebral artery occlusion in the rat. J Cereb Blood Flow Metab. 1992;12:621-628. [Medline] [Order article via Infotrieve]
3. Garcia JH, Kamijyo Y. Cerebral infarction: evolution of histopathological changes after occlusion of a middle cerebral artery in primates. J Neuropathol Exp Neurol. 1974;33:409-421.
4.
Hallenbeck JM, Dutka AJ, Tanishima T, Kochanek PM,
Kumaroo KK, Thompson C, Obrenovitch TP, Contreras TJ.
Polymorphonuclear leukocyte accumulation in brain regions
with low blood flow during the early postischemic
period. Stroke. 1986;17:246-253.
5. Price TH, Beatty PG, Corpuz SR. In vivo inhibition of neutrophil function in the rabbit using monoclonal antibody to CD18. J Immunol. 1987;139:4174-4177. [Abstract]
6. Youker K, Smith CW, Anderson DC, Miller D, Michael LH, Rossen RD, Entman ML. Neutrophil adherence to isolated adult cardiac myoctyes: induction by cardiac lymph collected during ischemia and reperfusion. J Clin Invest. 1992;89:602-609.
7. Zimmerman GA, Mclntyre TM. Neutrophil adherence to human endothelium in vitro occurs by CDw18 (Mol, MAC-1/LFA-1/GP150, 95) glycoprotein-dependent and -independent mechanisms. J Clin Invest. 1988;81:531-537.
8. Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol. 1986;137:1270-1274. [Abstract]
9. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer TA. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986;137:245-254. [Abstract]
10. Smith CW, Rothlein R, Hughes BJ, Mariscalco MM, Schmalstieg FC, Anderson DC. Recognition of an endothelial determinant for CD18 dependent human neutrophil adherence and transendothelial migration. J Clin Invest. 1988;82:1746-1756.
11. Staunton DE, Merluzzi VJ, Rothlein R, Barton R, Marlin SD, Springer TA. A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell. 1989;56:849-853. [Medline] [Order article via Infotrieve]
12. Bowes MP, Zivin JA, Rothlein R. Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. Exp Neurol. 1993;119:215-219. [Medline] [Order article via Infotrieve]
13. Clark WM, Madden KP, Rothlein R, Zivin JA. Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule. J Neurosurg. 1991;75:623-627. [Medline] [Order article via Infotrieve]
14.
Zhang RL, Chopp M, Li Y, Zaloga C, Jiang M, Jones M,
Miyasaka M, Ward P. Anti-ICAM-1 antibody reduces
ischemic cell damage after transient middle cerebral artery
occlusion in the rat. Neurology. 1994;44:1747-1751.
15.
Zea Longa Z, Weinstein PR, Carlson S, Cummins R.
Reversible middle cerebral artery occlusion without craniectomy
in rats. Stroke. 1989;20:84-91.
16. Tamatani T, Miyasaka M. Identification of monoclonal antibody reactive with the rat homologue of ICAM-1, and evidence for differential involvement of ICAM-1 in the adherence of resting versus activated lymphocytes to high endothelial cells. Int Immunol. 1993;2:166-172.
17. Kita Y, Takashi T, Iigo Y, Tamatani T, Miyasaka M, Horiuchi T. Sequence and expression of rat ICAM-1. Biochim Biophys Acta. 1992;1131:108-110. [Medline] [Order article via Infotrieve]
18. Zhang ZG, Chopp M, Chen H. Duration dependent post-ischemic hypothermia alleviates cortical damage after transient middle cerebral artery occlusion in the rat. J Neurol Sci. 1993;117:240-244. [Medline] [Order article via Infotrieve]
19. Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab. 1990;10:290-293. [Medline] [Order article via Infotrieve]
20. Jiang N, Zhang RL, Chen H, Chopp M. Anti-CD11B monoclonal antibody reduces ischemic cell damage after transient (2h) but not after permanent MCA occlusion in the rat. Neurosci Res Commun. 1994;15:85-94.
21. Werns SW, Lucchesi BR. Leukocytes, oxygen radical, and myocardial injury due to ischemia and reperfusion. Free Radic Biol Med. 1988;4:31-37. [Medline] [Order article via Infotrieve]
22. Ferrante A, Kowanko IC, Bates EJ. Mechanisms of host tissue damage by cytokine-activated neutrophils. Immunol Ser. 1992;57:499-521. [Medline] [Order article via Infotrieve]
23. Zhang RL, Chopp M, Chen H, Garcia JH. Temporal profile of ischemic tissue damage, neutrophil response, and vascular plugging following permanent and transient (2H) middle cerebral artery occlusion in the rat. J Neurol Sci. 1994;125:3-10. [Medline] [Order article via Infotrieve]
24. Ames A, Wright L, Kowade M, Thurston JM, Majors G. Cerebral ischemia: the no-reflow phenomenon. Am J Pathol. 1968;52:437-453. [Medline] [Order article via Infotrieve]
25.
Arfors K, Lundberg C, Lindbom L, Lundberg K, Beatty PG,
Harlan J. A monoclonal antibody to the membrane
glycoprotein complex CD18 inhibits PMN accumulation and
plasma leakage in vivo. Blood. 1987;69:338-340.
26.
Hernandez LA, Grisham MB, Twohic B, Arfors KE, Harlan
JM, Granger DN. Role of neutrophils in
ischemia-reperfusion-induced microvascular injury.
Am J Physiol. 1987;253:H699-H703.
27. Harlan J. Leukocyte-endothelial interaction. J Am Soc Hematol. 1985;65:513-525.
28. Harlan J. Neutrophil mediated vascular injury. Acta Med Scand. 1985;715:123-129.
29. Schmid-Schonbein G. Capillary plugging by granulocytes and the no-reflow phenomenon in the microcirculation. FASEB J. 1987;46:2397-2401.
30. Janoff A, Zweifach B. Production of inflammatory changes in the microcirculation by cationic proteins extracted from lysosomes. J Exp Med. 1964;120:747-764. [Abstract]
31. Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF III. Anti-CD11b monoclonal reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol. 1994;35:447-452.
32. Chopp M, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR. Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in the rat. Stroke. 1994;25:869-876. [Abstract]
33. Dietrich WD, Busto R, Alonso O, Globus MY-T, Ginsberg MD. Intraischemic but not postischemic brain hypothermia protects chronically following global forebrain ischemia in rat. J Cereb Blood Flow Metab. 1993;13:541-549. [Medline] [Order article via Infotrieve]
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N. Kawai, M. Okauchi, K. Morisaki, S. Nagao, and W. D. Dietrich Effects of Delayed Intraischemic and Postischemic Hypothermia on a Focal Model of Transient Cerebral Ischemia in Rats Editorial Comment Stroke, August 1, 2000; 31(8): 1982 - 1989. [Abstract] [Full Text] [PDF]
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 A. D. Blann and G. Y. H. Lip Editorial: Cell Adhesion Molecules in Cardiovascular Disease and Its Risk Factors--What Can Soluble Levels Tell Us? J. Clin. Endocrinol. Metab., May 1, 2000; 85(5): 1745 - 1747. [Full Text]
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D. C. Hess, E. Howard, C. Cheng, J. Carroll, W. D. Hill, and C. Y. Hsu Hypertonic Mannitol Loading of NF-{kappa}B Transcription Factor Decoys in Human Brain Microvascular Endothelial Cells Blocks Upregulation of ICAM-1 Editorial Comment Stroke, May 1, 2000; 31(5): 1179 - 1186. [Abstract] [Full Text] [PDF]
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 P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]
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M. Ishikawa, E. Sekizuka, S. Sato, N. Yamaguchi, J. Inamasu, H. Bertalanffy, T. Kawase, and C. Iadecola Effects of Moderate Hypothermia on Leukocyte- Endothelium Interaction in the Rat Pial Microvasculature After Transient Middle Cerebral Artery Occlusion • Editorial Comment Stroke, August 1, 1999; 30(8): 1679 - 1686. [Abstract] [Full Text] [PDF]
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J. Vogel, C. Mobius, W. Kuschinsky, and W. I. Rosenblum Early Delineation of Ischemic Tissue in Rat Brain Cryosections by High-Contrast Staining • Editorial Comment Stroke, May 1, 1999; 30(5): 1134 - 1141. [Abstract] [Full Text] [PDF]
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R. L. Zhang, Z. G. Zhang, M. Chopp, and J. A. Zivin Thrombolysis With Tissue Plasminogen Activator Alters Adhesion Molecule Expression in the Ischemic Rat Brain • Editorial Comment Stroke, March 1, 1999; 30(3): 624 - 629. [Abstract] [Full Text] [PDF]
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 A. D BLANN and G. Y H LIP Cell adhesion molecules in cardiovascular disease: what can soluble levels tell us? Heart, January 1, 1999; 81(1): 101 - 102. [Full Text]
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R. L. Zhang, Z. G. Zhang, and M. Chopp Increased therapeutic efficacy with rt-PA and anti-CD18 antibody treatment of stroke in the rat Neurology, January 1, 1999; 52(2): 273 - 273. [Abstract] [Full Text]
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A. Bitsch, W. Klene, L. Murtada, H. Prange, and P. Rieckmann A Longitudinal Prospective Study of Soluble Adhesion Molecules in Acute Stroke Stroke, October 1, 1998; 29(10): 2129 - 2135. [Abstract] [Full Text] [PDF]
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J. R. Bethea, M. Castro, R. W. Keane, T. T. Lee, W. D. Dietrich, and R. P. Yezierski Traumatic Spinal Cord Injury Induces Nuclear Factor-kappa B Activation J. Neurosci., May 1, 1998; 18(9): 3251 - 3260. [Abstract] [Full Text] [PDF]
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 L. Pantoni, C. Sarti, and D. Inzitari Cytokines and Cell Adhesion Molecules in Cerebral Ischemia : Experimental Bases and Therapeutic Perspectives Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 503 - 513. [Abstract] [Full Text] [PDF]
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 A. Martin-Ancel, A. Garcia-Alix, D. Pascual-Salcedo, F. Cabanas, M. Valcarce, and J. Quero Interleukin-6 in the Cerebrospinal Fluid After Perinatal Asphyxia Is Related to Early and Late Neurological Manifestations Pediatrics, November 1, 1997; 100(5): 789 - 794. [Abstract] [Full Text] [PDF]
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C.J.M. Frijns, L.J. Kappelle, J. v. Gijn, H.K. Nieuwenhuis, J.J. Sixma, and R. Fijnheer Soluble Adhesion Molecules Reflect Endothelial Cell Activation in Ischemic Stroke and in Carotid Atherosclerosis Stroke, November 1, 1997; 28(11): 2214 - 2218. [Abstract] [Full Text]
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E. M. Oshiro, P. A. Hoffman, G. N. Dietsch, M. C. Watts, D. M. Pardoll, and R. J. Tamargo Inhibition of Experimental Vasospasm With Anti-Intercellular Adhesion Molecule-1 Monoclonal Antibody in Rats Stroke, October 1, 1997; 28(10): 2031 - 2038. [Abstract] [Full Text]
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