Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocytes recruited during ischemia-reperfusion to the liver are important mediators of injury. However, the mechanisms of leukocyte adhesion and the role of adhesion receptors in hepatic vasculature remain elusive. L-selectin may critically contribute to injury, priming adhesion for later action of intercellular adhesion molecule-1 (ICAM-1). Paired experiments were performed using mutant mice (L-selectin -/-, ICAM-1 -/-, and L-selectin/ICAM-1 -/-) and wild-type mice (C57BL/6) to investigate leukocyte adhesion in the ischemic liver. Leukocyte adhesion and infiltration were assessed histologically. Aspartate aminotransferase levels were significantly reduced (2- to 3-fold) in mutant vs. wild-type mice in most groups but most significantly after 90 min of partial hepatic ischemia. Leukocyte adhesion was significantly reduced in all mutant mice. Areas of microcirculatory failure, visualized by intravital microscopy, were prevalent in wild-type but virtually absent in L-selectin-deficient mice. After total hepatic ischemia for 75 or 90 min, survival was better in mutant L-selectin and L-selectin/ICAM-1 mice vs. wild-type mice and ICAM-1 mutants. In conclusion, L-selectin is critical in the pathogenesis of hepatic ischemia-reperfusion injury. Poor sinusoidal perfusion due to leukocyte adhesion and clot formation is a factor of injury and appears to involve L-selectin and ICAM-1 receptors.
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PMID:L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. 984 71

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. In animal models of global and focal cerebral ischemia, numerous preclinical studies have demonstrated various agents to be neuroprotective at different steps along this cascade. A wide variety of drugs has also been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They include calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilizad, anti-intercellular adhesion molecule-1 (ICAM-1) antibody, GM-1 ganglioside, clomethiazole, the sodium channel antagonist fosphenytoin, and piracetam. In the future, clinicians may have an armamentarium of treatments for acute ischemic stroke at their disposal, with a combination of agents directed at different sites in the ischemic cascade being the ultimate goal.
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PMID:Neuroprotective therapy. 993 19

Our previous studies have demonstrated that overexpression of recombinant human interleukin-1 receptor antagonist protein (IL-1ra) via gene transfer can reduce ischemic brain injury. However, the mechanism of action of IL-1ra in ischemia is unclear. Since interleukin-1 can up-regulate intercellular adhesion molecules in endothelium, the present study was designed to determine whether overexpression of the IL-1ra can reduce the expression of intercellular adhesion molecule-1 (ICAM-1) after ischemic injury. Normal saline or adenovirus vector (1x109 particles) encoding the human IL-1ra gene (Ad.RSVIL-1ra) or the Escherichia coli LacZ gene (Ad.RSVlacZ) was injected into the right lateral cerebral ventricle of adult CD-1 mice. After five days, permanent middle cerebral artery occlusion (MCAO) was achieved for 24 h using an intraluminal suture. Cerebral blood flow was monitored by transcranial laser Doppler flowmetry to verify the occlusion. ICAM-1 protein was quantified using Western blot analysis and localized using immunohistochemistry. After MCAO, surface blood flow in the ischemic hemisphere was decreased to 9-11% of the baseline. There were fewer ICAM-1 positive vessels in the ischemic cortex of the Ad.RSVIL-1ra transfected mice than in the Ad.RSVlacZ transfected and saline treated mice (138+/-19 vs. 249+/-25, 284+/-22, p<0.05). Western blot analysis shows that ICAM-1 protein decreased 50-60% in the Ad. RSVIL-1ra group compared to the other two groups. There were no significant differences in the numbers of positive vessels in the ischemic basal ganglia and contralateral hemisphere among the three groups. Our studies suggest that IL-1ra overexpression can down-regulate the expression of ICAM-1 in the ipsilateral cortex in ischemic mice. Interleukin-1 may play an important role in the activation of inflammatory reaction during focal cerebral ischemia by promoting leukocyte adhesion on the endothelium cells.
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PMID:Expression of intercellular adhesion molecule 1 (ICAM-1) is reduced in permanent focal cerebral ischemic mouse brain using an adenoviral vector to induce overexpression of interleukin-1 receptor antagonist. 1006 85

-During myocardial reperfusion, polymorphonuclear neutrophil (PMN) adhesion involving the intercellular adhesion molecule-1 (ICAM-1) may lead to aggravation and prolongation of reperfusion injury. We studied the role of early tumor necrosis factor-alpha (TNF-alpha) cleavage and nuclear factor-kappaB (NF-kappaB) activation on ICAM-1 expression and venular adhesion of PMN in isolated hearts after ischemia (15 minutes) and reperfusion (30 to 480 minutes). NF-kappaB activation (electromobility shift assay) was found after 30 minutes of reperfusion and up to 240 minutes. ICAM-1 mRNA, assessed by Northern blot, increased during the same interval. Functional effect of newly synthesized adhesion molecules was found by quantification (in situ fluorescence microscopy) of PMN, given as bolus after ischemia, which became adherent to small coronary venules (10 to 50 microm in diameter). After 480 minutes of reperfusion, ICAM-1-dependent PMN adhesion increased 2.5-fold compared with PMN adhesion obtained during acute reperfusion. To study the influence of NF-kappaB on PMN adhesion, we inhibited NF-kappaB activation by transfection of NF-kappaB decoy oligonucleotides into isolated hearts using HJV-liposomes. Decoy NF-kappaB but not control oligonucleotides blocked ICAM-1 upregulation and inhibited the subacute increase in PMN adhesion. Similar effects were obtained using BB 1101 (10 microg), an inhibitor of TNF-alpha cleavage enzyme. These data suggest that ischemia and reperfusion in isolated hearts cause liberation of TNF-alpha, activation of NF-kappaB, and upregulation of ICAM-1, an adhesion molecule involved in inflammatory response after ischemia and reperfusion.
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PMID:Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts. 1006 73

MCAF (monocyte chemotactic and activating factor)/MCP-1 (monocyte chemoattractant protein-1) is an important mediator of monocyte recruitment to inflammatory sites. However, its pathophysiologic role in myocardial reperfusion injury remains unknown. Male Wistar rats were anesthetized, and the left anterior descending coronary artery was ligated for an hour, after which the ligature was released. Northern blotting analysis revealed that MCAF/MCP-1 mRNA expression increased 16-fold in the reperfused region at 12 hours after reperfusion. MCAF/MCP-1 concentration in plasma and the heart was already elevated after hour of ischemia in this model. Goat polyclonal antibodies were prepared by repeated immunization of animals with purified, recombinant rat MCAF/MCP-1, and the neutralizing activities of this antibody were confirmed by monocyte chemotaxis assay and administration to rats with crescentic glomerulonephritis. Intravenous injection of anti-MCAF/MCP-1 antibody significantly reduced the infarct size at 24 hours after reperfusion compared with the injection of control IgG (33.9 +/- 5.1% vs 49.4 +/- 2.7% of ischemic area, mean +/- SEM). Administration of this antibody markedly decreased the intercellular adhesion molecule-1 mRNA expression and infiltration of macrophages, which suggested the pathophysiologic role of MCAF/MCP-1. Neutralization of MCAF/MCP-1 is beneficial by preventing reperfusion injury in a rat model of myocardial ischemia and reperfusion.
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PMID:Prevention of myocardial reperfusion injury in rats by an antibody against monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. 1006 7

Leukocyte infiltration plays a major role in ischemia-associated organ dysfunction and damage. A crucial step for extravasation of white blood cells is binding of leukocyte beta-integrins to endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1). To test for direct effects of oxygen on this process we studied ICAM-1 and VCAM-1 expression in human dermal microvascular and umbilical vein endothelial cells (EC) exposed to different oxygen tensions in the absence or presence of tumor necrosis factor-alpha (TNF-alpha). Hypoxia (95% N2-5% CO2) resulted in a downregulation of basal but not TNF-alpha-induced expression of ICAM-1 and VCAM-1. Subsequent rises in oxygen (21, 40, or 95% O2) led to marked increase of ICAM-1 and VCAM-1 cell surface and mRNA expression in both EC types, which after 16 h amounted to about one-third to one-half of maximal TNF-alpha-induced expression. This increase was greatest after 0.5-h hypoxia and was blunted with prolonged hypoxic preincubation. Exposure of cells preincubated under "normoxic" (21% O2) conditions to hyperoxia (40 or 95% O2) also enhanced expression of both adhesion molecules, but the increase was lower than in cells preexposed to hypoxia. The nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) enhanced ICAM-1 and VCAM-1 expression under basal and hypoxic conditions, but in the presence of L-NAME, levels in reoxygenated cells were not higher than basal levels. Moreover, the oxygen-induced rise could be mimicked by addition of H2O2 to normoxic cells, and the oxygen-induced expression of VCAM-1 but not of ICAM-1 was inhibited by addition of the free radical scavengers superoxide dismutase, N-acetyl-L-cysteine, and pyrrolidinedithiocarbamate. These data indicate that an increase in oxygen availability stimulates ICAM-1 and VCAM-1 expression on micro- and macrovascular EC, which may contribute to adhesion and transmigration of different leukocyte populations in ischemia-reperfusion injuries.
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PMID:Increases in oxygen tension stimulate expression of ICAM-1 and VCAM-1 on human endothelial cells. 1036 86

Ischemia and reperfusion (I/R) induces neutrophil infiltration in skeletal muscle that is localized to the ischemic region. To transmigrate at ischemic regions, granulocytes must first arrest in the postcapillary venular segment of the microcirculation. Initially, leukocytes roll along the endothelium of these venules, a weak adhesive interaction that is mediated by the selectins (L-, E-, and P-selectin). Leukocyte rolling functions to slow the neutrophil during its transit through the microcirculation, thereby allowing it to monitor its local environment for the presence of activating factors arising from the ischemic tissues. When activated, the rolling granulocyte is rendered capable of forming the stronger adhesive interactions that allow the cell to become arrested in postcapillary venules in the ischemic region. These adhesive interactions are mediated by a leukocyte glycoprotein complex designated CD11/CD18 and intercellular adhesion molecule-1 (ICAM-1) expressed on endothelial cells. The stationary neutrophil uses the gradient in concentration of soluble chemoattractants liberated from ischemic tissues as a directional cue to move from the vascular to extravascular compartment, being guided in its transit across the endothelium by interactions with platelet endothelial cell adhesion molecule-1 (PECAM-1), an adhesive molecule localized to the interendothelial cleft. This paper reviews current understanding of the mechanisms underlying the establishment of leukocyte/endothelial cell interactions in postischemic skeletal muscle in terms of specific adhesion molecules that participate in neutrophil sequestration after I/R. Discovery of the molecular determinants of neutrophil/endothelial cell adhesion has uncovered potential mechanisms whereby agents exhibiting anti-adhesive properties may act. The micronized purified flavonoid fraction (450 mg diosmin, 50 mg hesperidin) prevents I/R-induced leukocyte adhesion in skeletal muscle. This anti-adhesive effect appears to be mediated at least in part by inhibition of induced expression of ICAM-1.
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PMID:Adhesion molecule expression in postischemic microvascular dysfunction: activity of a micronized purified flavonoid fraction. 1047 47

We and others have previously demonstrated that intestinal ischemia-reperfusion (I/R) is associated with a large increase in oxidant production that contributes to microvascular barrier disruption in the small bowel. It has been suggested that the bulk of tissue damage during reperfusion can be attributed to adherent, activated neutrophils. From these observations, we hypothesized that pretreatment with PR-39, an endogenous neutrophil antibacterial peptide that is also a potent inhibitor of the neutrophil NADPH oxidase, would prevent postischemic oxidant production and the development of oxidant-dependent sequelae to I/R such as increased venular protein leakage. To test this postulate, oxidant production, venular protein leakage, leukocyte adhesion, and leukocyte emigration were monitored during reperfusion in control (no ischemia) rat mesenteric venules and in mesenteric venules subjected to I/R alone or PR-39 + I/R. Treatment with a single intravenous bolus injection of PR-39 (administered at a dose to achieve an initial blood concentration of 5 microM) abolished I/R-induced leukocyte adhesion and emigration in vivo. In vitro studies indicated that PR-39 prevents platelet-activating factor-induced neutrophil chemotaxis as well as phorbol myristate acetate (PMA)-stimulated intercellular adhesion molecule-1 expression by cultured endothelial cells. PR-39 pretreatment of rat neutrophils also blocked PMA-stimulated neutrophil adhesion to activated endothelial monolayers. In vivo, I/R was associated with a marked and progressive increase in oxidant production and venular protein leakage during reperfusion, effects that were abolished by PR-39 treatment. The results of this study indicate that PR-39 completely abolishes postischemic leukocyte adhesion and emigration. The time course for inhibition of oxidant production by PR-39 suggests that its antiadhesive properties account for this effect of the peptide. PR-39 may thus be therapeutically useful for prevention of neutrophil adhesion and activation during the postischemic inflammatory response.
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PMID:PR-39, a proline/arginine-rich antimicrobial peptide, prevents postischemic microvascular dysfunction. 1048 23

Interleukin-1beta (IL-1beta) is expressed after cerebral ischemia and blocking its action reduces subsequent ischemic brain injury. However, the mechanisms by which IL-1beta affects ischemic brain are not understood. To investigate the role of IL- 1beta in regulation of tumor necrosis factor-alpha (TNF-alpha) and intercellular adhesion molecule-1 (ICAM-1) during focal cerebral ischemia, the authors studied mutant mice deficient in the IL-1 converting enzyme (ICE) gene (ICE knockout [KO] mice). Ninety-four adult male ICE KO and wild-type mice underwent 3, 6, 12, and 24 hours of permanent middle cerebral artery occlusion using the suture method. Expression of TNF-alpha and ICAM-1 protein in ischemic brain was examined using immunohistochemistry and Western blot analysis. Neither ICE KO nor wild-type mice had significant differences in CBF and body temperature measurements during the ischemic procedure. TNF-alpha expression increased in the ipsilateral hemisphere after 3 hours of occlusion, peaked at 12 hours and decreased at 24 hours of ischemia in both ICE KO and wild-type mice. ICAM-1 immunohistochemistry showed that the number of ICAM-1-positive vessels in the ischemic hemisphere was reduced in ICE KO mice (P < .05). Western blot analysis showed that ICAM-1 protein expression was significantly attenuated in the ipsilateral hemisphere in the ICE KO mice, which paralleled the immunohistochemistry results. The authors' results indicate that TNF-alpha expression is increased in both ICE KO and wild-type mice suggesting that TNF-alpha expression is not related to or upregulated by IL-1beta . ICAM-1 expression is significantly reduced in the ICE KO mice suggesting that IL-1beta plays an important role in the upregulation of adhesion molecules during focal cerebral ischemia.
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PMID:Expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-1beta converting enzyme deficient mice. 1053 35

We investigated the pathological appearance of acute inflammation and its role in the development of demyelination in reperfused rat sciatic, tibial, and peroneal nerves after a 5-hour period of near-complete ischemia. Polymorphonuclear neutrophil migration was seen early in the endoneurial lesion. After 18 hours of reperfusion, there was maximal intercellular adhesion molecule-1 expression on endoneurial vessels, and polymorphonuclear neutrophil accumulation was then prominent, reaching a peak 24 hours after reperfusion. Endoneurial mononuclear macrophages increased nearly fourfold after 48 to 72 hours of reperfusion. Macrophages were observed invading Schwann cells and myelin lamellae with associated demyelination. Thus, this study provides evidence of macrophage-associated demyelination after reperfusion similar to that seen in inflammatory neuropathies.
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PMID:Acute inflammatory demyelination in reperfusion nerve injury. 1063 3


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