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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The contribution of the immune system to the pathogenesis of ischemic lesions is still uncertain. We have analyzed leukocyte infiltration in photochemically induced focal ischemia of the rat parietal cortex by immunocytochemistry. Between 1 and 2 days after photothrombosis, CD5+ T cells adhered to subpial and cortical vessels and infiltrated the ischemic lesion prior to macrophages. By day 3 numerous T cells and some macrophages, whose number increased further between day 3 and day 7, had infiltrated the border zone around the lesion sparing the center. In addition, CD5-/CD8+ lymphocytes that probably represent natural killer cells were found. Intercellular adhesion molecule-1 (ICAM-1) was expressed on endothelial cells on days 1 and 2 and in the border zone on infiltrating leukocytes from day 3 to day 7. Starting on day 7, macrophages infiltrated the core of the lesion to remove debris. When the entire lesion was covered by macrophages at day 14, the number of T cells had decreased and ICAM-1 immunoreactivity was no longer found in or around the infarct. In conclusion, our study shows that ischemic lesions can lead to a local immune reaction in the CNS. Thus, blocking of lymphocyte-derived cytokines or cell adhesion molecules may provide a new approach to confining the sequelae of stroke.
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PMID:Lymphocytic infiltration and expression of intercellular adhesion molecule-1 in photochemically induced ischemia of the rat cortex. 752 23

We evaluated the ability of monoclonal antibodies directed against leukocyte adhesion molecules (intercellular adhesion molecule-1 [ICAM-1], CD18) to enhance the efficacy of thrombolysis in a rabbit cerebral embolism stroke model. Both tissue-type plasminogen activator (tPA) and anti-CD18 (alpha-CD18) monoclonal antibody administered 5 minutes after embolization increased the quantity of clots required to produce neurologic damage, although the combination was no more effective than either substance alone. Neither alpha-CD18 nor anti-ICAM-1 (alpha-ICAM-1) improved neurologic outcome at postischemic delays of 15 or 30 minutes. However, the combination of alpha-ICAM-1 (15 minutes after embolization) and tPA (2 hours after embolization) significantly improved neurologic outcome even though neither substance was effective alone at these postembolization delays. These findings suggest that prevention of leukocyte adhesion increases the postischemic duration at which thrombolytic therapy remains effective.
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PMID:Monoclonal antibodies preventing leukocyte activation reduce experimental neurologic injury and enhance efficacy of thrombolytic therapy. 772 76

Calcium is considered a mediator of ischemic brain damage whether this is due to global or forebrain ischemia or to focal ischemia. Supporting evidence is the translocation of extracellular calcium into cells during ischemia, the precipitous rise in the free cytosolic calcium concentration, and the role of calcium in activating lipases, proteases, kinases, phosphatases, and endonucleases in potentially harmful metabolic cascades. In vitro and in vivo experiments suggest that the main route of entry is through channels gated by glutamate receptors. These experiments led to the excitotoxic hypothesis of cell death. The in vitro experiments further support the role of calcium as a mediator of cell death. Both cell calcium overload and acidosis enhance the production of partially reduced oxygen species, thus predisposing to free radical-related damage. In transient global or forebrain ischemia, free radicals formed during reperfusion may contribute to a perturbed membrane function, leading to a sustained alteration of cell calcium metabolism with ultimate mitochondrial calcium overload. In focal ischemia (stroke), free radicals may be important mediators of the infarction process. Infarction can be regarded as a form of secondary damage, which is probably caused by microvascular dysfunction. Very likely, such dysfunction is triggered by upregulation of adhesion molecules such as ICAM-1, microvascular "plugging," and an inflammatory response at the blood-endothelial cell interface. The involvement of free radicals in this type of secondary damage is supported by results showing that nitrones that act as free radical spin-traps ameliorate focal ischemic damage with a therapeutic window of many hours.
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PMID:Glutamate, calcium, and free radicals as mediators of ischemic brain damage. 773 60

There is evidence that leukocytes play an important role in mediating tissue injury during acute ischemic stroke. Endothelial cell adhesive molecules such as ICAM-1 are required for the migration of leukocytes into the brain. Using an Elisa, we compared the expression of ICAM-1 by human brain microvascular endothelial cells with human umbilical vein endothelial cells. There was constitutive surface expression of ICAM-1 on both brain and umbilical vein endothelial cells. With cytokine (IL-1 beta or TNF) or lipopolysaccaride stimulation, ICAM-1 surface expression increased to a greater extent on brain than on umbilical vein endothelial cells. Dexamethasone at doses up to 100 microM had no effect on inhibiting cytokine-mediated upregulation of ICAM-1 on human brain microvascular endothelial cells.
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PMID:ICAM-1 expression on human brain microvascular endothelial cells. 791 16

We evaluated the effect of antibodies directed against a leukocyte adhesion molecule (ICAM-1) in an embolic model of stroke followed by thrombolysis with tissue plasminogen activator (tPA). To test whether reperfusion injury after ischemia was related to white cell adhesion, microclots were injected into carotid circulation. The conditions examined were control, alpha-ICAM 5 min following ischemia, tPA 30 min after ischemia, and the combination of alpha-ICAM and tPA. alpha-ICAM and tPA both increased the amount of clot necessary to produce permanent neurological damage. Combined therapy was no more effective than either substance alone. A similar outcome was obtained when tPA was delayed until 90 min postischemia. When thrombolysis was delayed 3 h following embolism, neither tPA nor the tPA/alpha-ICAM combination reduced neurological damage. Thus, the alpha-ICAM antibody and tPA each effectively reduced neurological damage but the interaction was not significant.
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PMID:Monoclonal antibody to the ICAM-1 adhesion site reduces neurological damage in a rabbit cerebral embolism stroke model. 809 42

When activated neutrophils are recruited and bind to endothelial tissues, they release leukotrienes, proteolytic enzymes, and free radicals. The latter has been implicated in myocardial stunning following periods of ischemia and reperfusion, as may occur following cardiopulmonary bypass (CPB). The neutrophil surface complex CD11/CD18 promotes the neutrophil-endothelial adhesion process. Monoclonal antibodies have been developed that can block neutrophil adhesion to the endothelium by preventing CD11/CD18 binding to adhesion molecules (ICAM-1 or ELAM-1) located on endothelial cells. We used monoclonal IgG antibody 60.3 to block neutrophil adherence and thereby potentially reduce myocardial stunning. Pretreatment of rabbits subjected to myocardial ischemia/reperfusion with either monoclonal 60.3 or saline resulted in only a small increase in the rate of recovery of preload recruitable stroke work index during reperfusion. More severe occlusion may have been needed to see significant results. We also evaluated the effects of anti-neutrophil therapy in animal models of CPB. Rhesus monkeys were subjected to deep hypothermia and CPB, followed by 24 hours of fluid resuscitation. Animals receiving monoclonal 60.3 (N = 3) showed less weight gain, less infused resuscitative fluid, and higher terminal hematocrit and PaO2 than controls (N = 3). Antineutrophil therapy may prevent multiorgan system failure in certain high risk patients.
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PMID:Potential role of neutrophil anti-adhesion therapy in myocardial stunning, myocardial infarction, and organ dysfunction after cardiopulmonary bypass. 846 23

This article reviews the evidence that myocardial stunning during surgical reperfusion after coronary revascularization or heart transplantation is not strictly due to myocardial injury sustained during ischemia, but results from pathophysiological events triggered by reperfusion (reperfusion injury). In sheep, left ventricular (LV) dP/dt and stroke work were reduced up to 50%, and 60% to 70% necrosis was observed in the area at risk during 3 hours reperfusion following coronary occlusion and cardioplegic arrest on bypass. Reperfusion with leukocyte depleted blood, or pharmacological blockade of either thromboxane or leukotriene receptors, provided significant improvements in LV function and myocardial blood flow, with a 40% to 50% reduction in necrosis. Similar results have been obtained using animal heart subjected to 2 to 3 hours arrest at either 4 degrees C or 15 degrees C, simulating cardiac preservation and reperfusion after transplantation. Diastolic pressure was significantly elevated, and increases in the time constant for relaxation of LV pressure and coronary vascular resistance were noted. These indices of myocardial stunning were reversed after blocking neutrophil-endothelial cell interaction with monoclonal antibodies against CD18 or ICAM-1 receptors, and significant improvements were also obtained after either thromboxane or leukotriene receptor blockade. We conclude that immediate postoperative myocardial stunning results largely from reperfusion injury that occurs due to an acute inflammatory response to ischemia and reperfusion, and that stunning can be largely reversed with appropriate pharmacological intervention.
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PMID:Myocardial stunning and reperfusion injury in cardiac surgery. 846 24

Once thought as immunologically naive, cells from the central nervous system have been shown to become immunologically reactive and produce various substances including cytokines and adhesion molecules. Recent investigations have revealed that mRNAs of certain cytokines such as tumor necrosis factor, interleukin-1, and interleukin-6 are expressed in the ischemic brain of the animals. Chemokines including CINC, MCP-1, and MIP-1, as well as adhesion molecules such as ICAM-1. ELAM and P-selectin were also found to be expressed. Although identification of the cells producing these cytokines were often difficult, neurons, endothelia, activated astrocytes and microglia/macrophages were the likely sources. The induction of these molecules in ischemic brain is time-locked and appears to be controlled in a highly regulated manner during the process of ischemic cascade. The functional role, interrelationship, and basic mechanism of action of these molecules are being increasingly recognized, while trials such as antiadhesion antibody molecules, growth factors, and anticytokine antibodies have been successful in reducing the neuronal damage in animals subjected to ischemic injury. Furthermore, changes of certain cytokines or adhesion molecules have been detected in the serum or cerebrospinal fluid of patients with stroke and related diseases suggesting that these molecules play a role in the pathogenesis of human stroke. Understanding of these cytokine-adhesion molecule cascades in the ischemic brain may allow us to develop new strategies for the treatment of stroke.
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PMID:Cytokines and adhesion molecules in stroke and related diseases. 878 58

Leukocytes and their actions have been implicated in the pathogenesis of microcirculatory and cytotoxic perturbations in experimental stroke models. Experiments in several models of stroke pathophysiology have demonstrated the important role of endothelial intercellular adhesion molecule (ICAM-1) in targeting the leukocyte response to the ischemic brain region and transmigration of polymorphonuclears into the parenchyma. In this article, investigations suggesting beneficial effects of anti-adhesion therapies blocking the endothelial ICAM-1 or its counter-receptor CDII/CD18 on leukocytes are reviewed. This evidence should be viewed also in the context of human stroke, which has also recently been shown to overexpress ICAM-1 molecules on the infarcted endothelium. Well-tolerated monoclonal antibodies (mAb) blocking ICAM-1 might eventually be shown to possess therapeutic value acutely in clinical stroke victims, perhaps in combination with thrombolytic therapy.
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PMID:ICAM-1 as a potential target for treatments blocking the host response in stroke. 889 69

Adhesion and subsequent penetration of leukocytes into central nervous system ischemic tissue proceeds via a coordinated inflammatory mechanism involving adhesion molecules at the blood-endothelium interface. Mammalian hibernation is a state of natural tolerance to severely reduced blood flow-oxygen delivery (i.e., ischemia). Hibernating thirteen-lined ground squirrels were investigated in an attempt to identify factors responsible for regulating this tolerance. Since leukocytopenia is closely associated with entrance into hibernation, the role of leukocyte adhesion to endothelium in this phenomenon was examined. Intercellular adhesion molecule-1 (ICAM-1) is expressed by endothelium and regulates interactions with circulating leukocytes that may result in margination or extravasation. ICAM-1 expression by rat cerebral microvascular endothelial cells (EC) cultured with plasma from hibernating (HP) or nonhibernating (NHP) thirteen-lined ground squirrels was dose dependently increased by HP and, to a lesser extent, by NHP. Treatment of EC with HP coincidentally induced significantly greater increases in monocyte adhesion to EC (37.2%) than were observed with NHP (23.9%). Study of the effects of HP and NHP on monocyte adhesion to EC may identify mechanisms responsible for ischemic tolerance in hibernators and could lead to the development of novel therapeutic approaches to the treatment of stroke.
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PMID:Effects of plasma from hibernating ground squirrels on monocyte-endothelial cell adhesive interactions. 943 38


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