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

Extravasation of leukocytes at sites of ischemia may mediate tissue injury. To determine how leukocyte accumulation may be induced by ischemia, effects of hypoxia on basal neutrophil expression of adhesion and activation receptors were examined. Effects of hypoxia upon preactivated cells were also studied. To determine whether regulation of expression is dependent on oxygen availability or on mitochondrial respiration, the effects of physical hypoxia (substitution of O2 by nitrogen) were compared with those of chemical hypoxia with sodium cyanide (NaCN). Leukocytes in whole blood (eight volunteers) were exposed either to hypoxia alone or to priming concentrations of lipopolysaccharide (LPS, 1 microgram/ml) followed by chemical hypoxia (NaCN, 1 mM) or physical hypoxia (PO2 of 1-10 torr) for various time intervals. Room air was controlled and hypoxic cells were labeled with fluorescent monoclonal antibodies to integrins CD18 and CD11b or to the 55-kDa TNF alpha cell surface receptor (TNFR). Receptor concentrations were measured by flow cytometry. Data were analyzed by ANOVA/Student's t test. Physical hypoxia increased expression of both CD11b and CD18 over time and augmented their LPS-induced up-regulation. Isolated chemical hypoxia did not change neutrophil expression of CD11b or CD18, but partially inhibited neutrophil CD11b and CD18 up-regulation by LPS. LPS-induced TNFR down-regulation was not affected by physical hypoxia, which failed to alter TNFR expression in this model.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Hypoxia-induced alterations of neutrophil membrane receptors. 763 Jan 18

Platelet factor 4, which has a potent affinity for heparin, has been shown to inhibit the binding of basic fibroblast growth factor to the cell surface receptor and to counteract the biological activities of basic fibroblast growth factor in certain peripheral tissues. In the present in vitro [125I]basic fibroblast growth factor binding experiments, platelet factor 4 consistently inhibited the binding of iodinated basic fibroblast growth factor to cell membranes of the gerbil hippocampus. To investigate the in vivo function of endogenous basic fibroblast growth factor and/or basic fibroblast growth factor receptor possibly activated in the ischemic gerbil brain, we infused platelet factor 4 continuously into the left lateral ventricle with an osmotic minipump. When platelet factor 4 infusion was started within three days after a 3-min ischemic insult, it significantly enhanced ischemia-induced learning disability and ischemic neuronal loss in the CA1 region of the hippocampus, as demonstrated by the results of the step-down passive avoidance task and by subsequent histological examinations. Infusion of platelet factor 4 into the cerebral ventricle of intact gerbils did not affect learning ability or CA1 neuron number. Basic fibroblast growth factor-neutralizing antibody, when infused continuously in the cerebral ventricle, also exhibited a neurotoxic effect in ischemic but not intact gerbils. Basic fibroblast growth factor co-infused with heparin, but not basic fibroblast growth factor alone, rescued a significant number of ischemic neurons which were destined to degenerate without the infusion of heparinized basic fibroblast growth factor, and it prevented ischemia-induced learning disability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protective effect of basic fibroblast growth factor-heparin and neurotoxic effect of platelet factor 4 on ischemic neuronal loss and learning disability in gerbils. 777 64

Septic shock is an increasingly important clinical condition, characterized by systemic hypotension, ischemia, and ultimately organ failure. In Gram negative infection, the bacterial cell wall component, lipopolysaccharide (endotoxin, LPS), has been strongly linked to the pathophysiological responses that result in septic shock. LPS is bound in plasma to a protein called LPS-binding protein (LBP), which facilitates the binding of LPS to a cell surface receptor, CD14. Binding to CD14 stimulates cell signaling mechanisms that result in the production of inflammatory cytokines. However, the events which follow LPS binding to CD14 and which lead to the production of cytokines remain unclear. It has recently become evident that a number of phosphorylation cascades including MAP kinase pathways and NF-kappaB activation pathway are initiated by exposure of cells to LPS. These cascades act at both the transcriptional and translational levels to regulate cytokine production. This review will focus on the signaling pathways that are initiated by LPS and the cellular effects of the signaling pathways.
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PMID:Cellular activation mechanisms in septic shock. 956 Mar 58

Fas/CD95/Apo-1 is a cell surface receptor that transduces apoptotic death signals following activation and has been implicated in triggering apoptosis in infected or damaged cells in disease states. Apoptosis is a major mechanism of neuronal loss following hypoxic-ischemic injury to the developing brain, although the role of Fas in this process has not been studied in detail. In the present study, we have investigated the expression and function of Fas in neuronal cells in vitro and in vivo. Fas was found to be expressed in the 14 day old rat brain, with strongest expression in the cortex, hippocampus and cerebellum. Cross-linking of Fas induced neuronal apoptosis both in neuronal PC12 cells in culture and following intracerebral injection in vivo, indicating that neuronal Fas was functional as a death receptor. This death was shown to be caspase dependent in primary neuronal cultures and was blocked by the selective caspase 8 inhibitor IETD. Finally, cerebral hypoxia-ischemia resulted in a strong lateralised upregulation of Fas in the hippocampus, that peaked six to twelve hours after the insult and was greater on the side of injury. These results suggest that Fas may be involved in neuronal apoptosis following hypoxic-ischemic injury to the developing brain.
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PMID:Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain. 1066 92

Fas is a widely expressed cell surface receptor that can initiate apoptosis when activated by its ligand (FasL). Whereas Fas abundance on cardiac myocytes increases in response to multiple pathological stimuli, direct evidence supporting its role in the pathogenesis of heart disease is lacking. Moreover, controversy exists even as to whether Fas activation induces apoptosis in cardiac myocytes. In this study, we show that adenoviral overexpression of FasL, but not beta-galactosidase, results in marked apoptosis both in cultures of primary neonatal cardiac myocytes and in the myocardium of intact adult rats. Myocyte killing by FasL is a specific event, because it does not occur in lpr (lymphoproliferative) mice that lack functional Fas. To assess the contribution of the Fas pathway to myocardial infarction (MI) in vivo, lpr mice were subjected to 30 min of ischemia followed by 24 h of reperfusion. Compared with wild-type mice, lpr mice exhibited infarcts that were 62.3% smaller with 63.8% less myocyte apoptosis. These data provide direct evidence that activation of Fas can induce apoptosis in cardiac myocytes and that Fas is a critical mediator of MI due to ischemia-reperfusion in vivo.
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PMID:Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion in vivo. 1241 49

Preconditioning enables endogenous protection to repeated myocardial ischemia. However, the effect of preconditioning on beta1 adrenergic receptor (AR) signal remains controversial. We have recently developed receptor assay system using whole cells, in which overexpressed cell surface beta ARs can be readily quantitated without disrupting the cell. Using this technique, we examined the effects of chemical/metabolic ischemia on the beta1 AR sequestration and adenylyl cyclase activity. Isoproterenol treatment, but not forskolin treatment, of HEK293T cells overexpressing beta1 ARs led to a rapid decrease (within 2 hours) in the number of the cell surface receptor, which was negated in the presence of concanavalin A. Similarly, treatment of cells with potassium cyanide and 2-deoxy-D-glucose (chemical/metabolic ischemia) induced similar receptor sequestration. When isoproterenol was superimposed on chemical/metabolic ischemia, the degree of sequestration became greater. However, when cells were pre-exposed to potassium cyanide on the preceding day (chemical preconditioning), the sequestration induced by either isoproterenol or chemical/metabolic ischemia was attenuated. Adenylyl cyclase catalytic activity as assessed by stimulation with forskolin was decreased by chemical/metabolic ischemia but fully recovered after 24 hours, suggesting that chemical/metabolic ischemia treatment did not alter cell viability. Putting together, chemical/metabolic ischemia induced beta1 AR sequestration in a similar manner to isoproterenol. In addition, preconditioning prevented the beta1 AR sequestration induced by both isoproterenol and chemical/metabolic ischemia. Pre-conditioning may play a role in preserving the cell surface beta ARs by inhibiting the sequestration that is usually induced by an ischemic event or beta adrenergic stimulation.
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PMID:Ischemic preconditioning prevents ischemia-induced beta-adrenergic receptor sequestration. 1287 79

We previously reported that hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activated intracellular signaling such as mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated protein kinase (ERK) 1/2, p38MAPK, and stress-activated protein kinases (SAPKs). To investigate the humoral factors which mediate cardiac response to hypoxia/reoxygenation, we analyzed the conditioned media from cardiac myocytes subjected to hypoxia/reoxygenation by two-dimensional electrophoresis and mass spectrometry. We identified cyclophilin A (CyPA) as one of the proteins secreted from cardiac myocytes in response to hypoxia/reoxygenation. Hypoxia/reoxygenation induced the expression of CyPA and its cell surface receptor CD147 on cardiac myocytes in vitro. This was also confirmed by ischemia/reperfusion in vivo. Recombinant human (rh) CyPA activated ERK1/2, p38MAPK, SAPKs, and Akt in cultured cardiac myocytes. Furthermore, CyPA significantly increased Bcl-2 in cardiac myocytes. These data strongly suggested that CyPA is released from cardiac myocytes in response to hypoxia/reoxygenation and may protect cardiac myocytes from oxidative stress-induced apoptosis.
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PMID:Hypoxia followed by reoxygenation induces secretion of cyclophilin A from cultured rat cardiac myocytes. 1504 62

A loss of balance between excitatory and inhibitory signaling leads to excitoxicity, and contributes to ischemic cell death. Reduced synaptic inhibition as a result of dysfunction of the ionotropic GABAA receptor has been suggested as one of the major causes for this imbalance, although the underlying mechanisms remain poorly understood. In the present study, we investigated whether oxygen-glucose deprivation (OGD), an ischemia-like challenge, alters cell-surface expression of GABAA receptors in cultured hippocampal neurons, and thereby leads to excitotoxic cell death. Using cell culture ELISA as a cell surface receptor assay, we found that OGD produced a marked decrease in cell surface GABAA receptors, without altering the total amount of receptors. Furthermore, the reduction could be prevented by inhibition of receptor endocytosis with hypertonic sucrose treatment. Notably, insulin significantly limited OGD-induced changes in cell-surface GABAA receptors. In parallel, insulin protected cultured neurons against both glutamate toxicity and OGD, as assayed by mitochondrial reduction of Alamar Blue. Importantly, insulin-mediated neuroprotection was eliminated when bicuculline, a GABAA receptor antagonist, was co-applied with insulin during OGD. Together, our results strongly suggest that ischemia-like insults decrease cell surface GABAA receptors in neurons via accelerated internalization, and that insulin provides neuroprotection by counteracting this reduction.
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PMID:Insulin exerts neuroprotection by counteracting the decrease in cell-surface GABA receptors following oxygen-glucose deprivation in cultured cortical neurons. 1560

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts on responsive cells via binding to a small cell surface receptor named Fn14. Recent studies have demonstrated that TWEAK can stimulate numerous cellular responses including cell proliferation, migration, and proinflammatory molecule production, but the role of this cytokine in cardiovascular disease and stroke has not been established. The present study investigated whether TWEAK or Fn14 expression was regulated in a murine model of cerebral ischemia and whether TWEAK played a role in ischemia-mediated cell death. We found that TWEAK and Fn14 were expressed by primary mouse cerebral cortex-derived astrocytes and neurons cultured in vitro. Also, both the TWEAK and Fn14 proteins were present at elevated levels in the ischemic penumbra region after middle cerebral artery occlusion. Finally, we report that intracerebroventricular injection of a soluble Fn14-Fc decoy receptor immediately after middle cerebral artery occlusion significantly reduced infarct volume and the extent of microglial cell activation and apoptotic cell death in the ischemic penumbra. We conclude that the cytokine TWEAK may play an important role in ischemia-induced brain injury and that inhibition of TWEAK expression or function in the brain may represent a novel neuroprotective strategy to treat ischemic stroke.
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PMID:A soluble Fn14-Fc decoy receptor reduces infarct volume in a murine model of cerebral ischemia. 1568 34

The cell surface receptor alpha4 integrin plays a critical role in the homing, engraftment, and maintenance of hematopoietic progenitor cells (HPCs) in the bone marrow (BM). Down-regulation or functional blockade of alpha4 integrin or its ligand vascular cell adhesion molecule-1 mobilizes long-term HPCs. We investigated the role of alpha4 integrin in the mobilization and homing of BM endothelial progenitor cells (EPCs). EPCs with endothelial colony-forming activity in the BM are exclusively alpha4 integrin-expressing cells. In vivo, a single dose of anti-alpha4 integrin antibody resulted in increased circulating EPC counts for 3 d. In hindlimb ischemia and myocardial infarction, systemically administered anti-alpha4 integrin antibody increased recruitment and incorporation of BM EPCs in newly formed vasculature and improved functional blood flow recovery and tissue preservation. Interestingly, BM EPCs that had been preblocked with anti-alpha4 integrin ex vivo or collected from alpha4 integrin-deficient mice incorporated as well as control cells into the neovasculature in ischemic sites, suggesting that alpha4 integrin may be dispensable or play a redundant role in EPC homing to ischemic tissue. These data indicate that functional disruption of alpha4 integrin may represent a potential angiogenic therapy for ischemic disease by increasing the available circulating supply of EPCs.
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PMID:Functional disruption of alpha4 integrin mobilizes bone marrow-derived endothelial progenitors and augments ischemic neovascularization. 1640 93


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