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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Polymorphonuclear leukocyte (PMN) activation and PMN-endothelial cell interactions may cause graft failure due to ischemia-reperfusion injury after lung transplantation. We investigated the effects of Euro-Collins solution (EC), low-potassium dextran solution (LPD), and EC plus pentoxifylline (EC-PTXF) on adhesion molecule (CD11b/CD18 and L-selectin) expression, chemotaxis, and oxidative burst of PMN. PMN from healthy human volunteers were incubated with EC, LPD, and EC-PTXF, and, in controls, without preservation solution. LPD exerted a suppressive effect on PMN chemotaxis as compared to EC (P < 0.05), but had no attenuating effect on the increase of CD11b/CD18, the shedding of L-selectin, and intracellular oxidant generation. EC-PTXF attenuated the expression of CD11b/CD18 and the oxidative burst as compared to EC alone (P < 0.05). These effects of LPD and PTXF on PMN function may contribute to successful organ preservation in transplantation.
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PMID:Effects of lung preservation solutions on PMN activation in vitro. 1036 93

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 have recently reported that hepatic ischemia/reperfusion (I/R) is associated with a biphasic increase in the expression of P-selectin in the liver microvasculature, with peak expression levels observed at 20 min and 5 h after reperfusion. This I/R-induced upregulation of P-selectin expression is accompanied by leukocyte-endothelial cell adhesion in terminal hepatic venules (THV). The objective of this study was to determine whether the early expression of P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in THV after liver I/R. Left hepatic lobe ischemia was induced for 30 min in anesthetized C57B1/6 and P-selectin knockout (KO) mice. The number of rolling, saltating, and adherent leukocytes in THV was measured at 0, 15, 30, 60, and 120 min after reperfusion using intravital video microscopy. Hepatic I/R elicited significant increases in the number of rolling, saltating, and adherent leukocytes, with peak values observed at 30 min after reperfusion. All of these responses were absent in P-selectin KO mice and in C57B1/6 mice treated with a blocking antibody to P-selectin. Our findings suggest that P-selectin is the primary determinant of leukocyte-endothelial cell adhesion observed in hepatic venules in the initial period after I/R. Hence, this adhesion molecule may represent a target for therapeutic intervention in liver transplantation and other conditions associated with hepatic I/R.
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PMID:P-selectin contributes to the initial recruitment of rolling and adherent leukocytes in hepatic venules after ischemia/reperfusion. 1048 3

The proinflammatory cytokine interleukin-1 beta (IL-1beta) is thought to play an important role in the stimulation of the inflammatory response following ischemia and reperfusion. This study investigated the inflammatory effect of IL-1beta during transient focal cerebral ischemia and reperfusion in the mouse transduced with the interleukin-1 receptor antagonist (IL-1ra) gene. An adenoviral vector encoding, either the human IL-1ra gene (AdRSVIL-1ra) or the LacZ gene (AdRSVlacZ) or normal saline, were injected into the right lateral ventricles of adult CD-1 mice (n=96). Five days later, the mice received 1 h temporary middle cerebral artery occlusion (tMACAO) followed by 23 h reperfusion. Cerebral blood flow (CBF), infarct volume, blood-brain barrier (BBB) permeability, and the number of intracellular adhesion molecule-1 positive vessels were measured to determine the effect of IL-1beta during postischemic reperfusion. Infarct volume in the AdRSVIL-1ra-transduced mice was markedly reduced compared to the AdRSVlacZ-transduced and saline-injected mice (36.0+/-5.3 mm(3) vs. 60.0+/-6.2 mm(3), 69. 5+/-6.3 mm(3), after 23 h of reperfusion, n=6-8 per group, p<0.05). BBB disruption and intracellular adhesion molecule-1 expression (135+/-23 vs. 311+/-40 and 357+/-51, n=6-8 per group, p<0.05) in the AdRSVIL-1ra-transduced mice were also less than that of the AdRSVlacZ-transduced and saline-injected mice. Our studies demonstrated that overexpression of IL-1ra in the mouse brain can downregulate intracellular adhesion molecule-1 expression both in the cortex and basal ganglia, which suggests that IL-1beta may play an important role in the activation of the inflammatory response during focal cerebral ischemia by promoting leukocyte adhesion to endothelial cells. The decrease of BBB disruption in AdRSVIL-1ra-transduced mice suggests that the endothelial cells may be a target for IL-1beta during postischemic reperfusion.
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PMID:Attenuation of temporary focal cerebral ischemic injury in the mouse following transfection with interleukin-1 receptor antagonist. 1052 71

Following ischemia-reperfusion (I/R), platelet adhesion is thought to represent the initial event leading to remodeling and reocclusion of the vasculature. The mechanisms underlying platelet adhesion to the endothelium have not been completely established. Endothelial cells rendered ischemic acquire a procoagulant phenotype, characterized by fibrinogen accumulation. Therefore, we evaluated whether fibrinogen deposition during I/R mediates platelet adhesion. Using fluorescence microscopy, fibrinogen deposition and the accumulation of platelets were assessed in vivo in a model of intestinal I/R (1.5 hours/60 minutes). Fibrinogen accumulated in arterioles and venules early after the onset of reperfusion. The deposition of fibrinogen colocalized with large numbers of adherent platelets (520 +/- 65 and 347 +/- 81 platelets/mm(2) in arterioles and venules). Pretreatment with an antifibrinogen antibody attenuated platelet adhesion. Intracellular adhesion molecule (ICAM)-1 served as a major receptor for fibrinogen, since fibrinogen deposition and platelet adhesion to the endothelial cell surface were markedly decreased in ICAM-1-deficient mice. The platelet alpha(IIb)/beta(3) integrin plays a key role in fibrinogen-dependent platelet accumulation, because (1) platelet adhesion involved RGD-recognition sequences, and (2) platelets isolated from a patient with Glanzmann's disease showed decreased interaction with the postischemic endothelium. Since platelets are demonstrated here to induce tyrosine phosphorylation in endothelial cells, platelet recruitment might contribute to the development of an inflammatory reaction during I/R.
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PMID:Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. 1057 98

Leukocyte infiltration into the brain has been implicated in the development of ischemic brain damage. In this study, simulated in vitro ischemia/reperfusion and IL-1beta were found to up-regulate both the expression of intercellular adhesion molecule- (ICAM-1) in cultured human cerebromicrovascular endothelial cells (HCEC) and the adhesion of allogenic neutrophils to HCEC. Both HCEC and human fetal astrocytes (FHAS) also responded to IL-1beta and to in vitro ischemia/reperfusion by a pronounced up-regulation of IL-8 and MCP-1 mRNA and by increased release of IL-8 and MCP-1 in cell culture media. FHAS were found to release 30-times higher levels of MCP-1 than HCEC under both basal and ischemic conditions. However, 100 u/ml IL-1beta induced greater stimulation of both IL-8 and MCP-1 secretion in HCEC (50 and 20 times above controls, respectively) than in FHAS (three and two times above controls, respectively). IL-8 was the principal neutrophil chemoattractant released from IL-1beta-treated HCEC, since IL-8 antibody completely inhibited neutrophil chemotaxis enticed by HCEC media. However, the IL-8 antibody neutralized only 50% of IL-1beta-stimulated neutrophil chemoattractants released from FHAS, and 40%-60% of ischemia-stimulated chemotactic activity released by either HCEC or FHAS. These results suggest that simulated in vitro ischemia, in addition to IL-8 and MCP-1, stimulates secretion of other bioactive chemokines from HCEC and FHAS.
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PMID:Increased expression of bioactive chemokines in human cerebromicrovascular endothelial cells and astrocytes subjected to simulated ischemia in vitro. 1058 Jul 98

Modification of gene expression within the heart could have a dramatic impact on both cardiac transplantation and routine cardiac surgery within the next decade. The advantage of gene therapy is that it would allow organ-selective local delivery of higher levels of cytokines, growth factors, vasodilators, or immunosuppressive drugs than could be safely achieved by systemic administration. Direct transfection or transduction of myocytes, endothelium, and/or vascular smooth muscle cells could increase the density of beta adrenergic receptors, inhibit endothelial adhesion molecule expression, or prevent neointimal formation in coronary bypass grafts. Cell transfer of neonatal or engineered adult myocytes might allow repopulation of infarct areas. The current limitations to effective clinical gene therapy are the variable transfection efficiencies of gene delivery systems, limited duration of gene expression, immune responses to viral vectors, and safety concerns. Ischemia-reperfusion injury will be one of the earliest applications for gene therapy since the short time course of injury and recovery would be amenable to therapeutic approaches with limited durations of action, achievable by currently available delivery vectors.
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PMID:Myocardial protection: is there a role for gene therapy? 1058 5

Reperfusion of ischemic myocardium is necessary to salvage tissue from eventual death. However, reperfusion after even brief periods of ischemia is associated with pathologic changes that represent either an acceleration of processes initiated during ischemia per se, or new pathophysiological changes that were initiated after reperfusion. This 'reperfusion injury' shares many characteristics with inflammatory responses in the myocardium. Neutrophils feature prominently in this inflammatory component of postischemic injury. Ischemia-reperfusion prompts a release of oxygen free radicals, cytokines and other proinflammatory mediators that activate both the neutrophils and the coronary vascular endothelium. Activation of these cell types promotes the expression of adhesion molecules on both the neutrophils and endothelium, which recruits neutrophils to the surface of the endothelium and initiate a specific cascade of cell-cell interactions, leading first to adherence of neutrophils to the vascular endothelium, followed later by transendothelial migration and direct interaction with myocytes. This specific series of events is a prerequisite to the phenotypic expression of reperfusion injury, including endothelial dysfunction, microvascular collapse and blood flow defects, myocardial infarction and apoptosis. Pharmacologic therapy can target the various components in this critical series of events. Effective targets for these pharmacologic agents include: (a) inhibiting the release or accumulation of proinflammatory mediators, (b) altering neutrophil or endothelial cell activation and (c) attenuating adhesion molecule expression on endothelium, neutrophils and myocytes. Monoclonal antibodies to adhesion molecules (P-selectin, L-selectin, CD11, CD18), complement fragments and receptors attenuate neutrophil-mediated injury (vascular injury, infarction), but clinical application may encounter limitations due to antigen-antibody reactions with the peptides. Humanized antibodies and non-peptide agents, such as oligosaccharide analogs to sialyl Lewis, may prove effective in this regard. Both nitric oxide and adenosine exhibit broad spectrum effects against neutrophil-mediated events and, therefore, can intervene at several critical points in the ischemic-reperfusion response, and may offer greater benefit than agents that interdict at a single point in the cascade. The understanding of the molecular processes regulating actions of neutrophils in ischemic-reperfusion injury may be applicable to other clinical situations, such as trauma, shock and organ or tissue (i.e. vascular conduits) transplantation.
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PMID:The role of neutrophils in myocardial ischemia-reperfusion injury. 1061 13

The aim of the present study was to investigate the protective effect of the pineal secretary product melatonin in a model of splanchnic artery occlusion shock (SAO). SAO shock was induced in rats by clamping both the superior mesenteric artery and the celiac trunk for 45 min, followed thereafter by release of the clamp (reperfusion). At 60 min after reperfusion, animals were sacrificed for tissue histological examination and biochemical studies. There was a marked increase in the oxidation of dihydrorhodamine 123 to rhodamine (a marker of peroxynitrite-induced oxidative processes) in the plasma of the SAO-shocked rats after reperfusion, but not during ischemia alone. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, an index of nitrogen species such as peroxynitrite, in the necrotic ileum in shocked rats. SAO-shocked rats developed a significant increase of tissue myeloperoxidase and malondialdehyde activity, and marked histological injury to the distal ileum. SAO shock was also associated with a significant mortality (0% survival at 2 hr after reperfusion). Reperfused ileum tissue sections from SAO-shocked rats showed positive staining for P-selectin, which was mainly localized in the vascular endothelial cells. Ileum tissue sections obtained from SAO-shocked rats with anti-intercellular adhesion molecule (ICAM-1) antibody showed a diffuse staining. Melatonin (applied at 3 mg/kg, 5 min prior to reperfusion, followed by an infusion of 3 mg/kg per hr), significantly reduced ischemia reperfusion injury in the bowel as evaluated by histological examination. This prevented the infiltration of neutrophils into the reperfused intestine, is evidenced by reduced myeloperoxidase activity and reduced lipid peroxidation. This was evaluated by malondialdehyde activity which reduced the production of peroxynitrite during reperfusion, markedly reduced the intensity and degree of P-selectin and ICAM-1 in tissue section from SAO-shocked rats and improved their survival. Taken together, our results clearly demonstrate that melatonin treatment exerts a protective effect and part of this effect may be due to inhibition of the expression of adhesion molecule and peroxynitrite-related pathways and subsequent reduction of neutrophil-mediated cellular injury.
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PMID:Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. 1062 2


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