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)

The objective of this study was to determine what roles the endothelial cell and inducible isoforms of nitric oxide synthase (eNOS, iNOS) play in ischemia and reperfusion (I/R)-induced liver injury in vivo in mice genetically deficient in each isoform of NOS. We found that 45 min of partial (70%) liver ischemia and 5 h of reperfusion induced substantial liver injury as assessed by the release of large and significant amounts of the liver-specific enzyme alanine aminotransferase (ALT) into the serum of wild-type (wt) mice. The enhanced ALT levels were not due to increased recruitment of potentially damaging PMNs, which could mediate hepatocyte injury, as neither histopathological inspection nor quantitative MPO determinations revealed the presence of PMNs in the liver at this time point. In addition, we observed a significant enhancement in liver injury in eNOS-deficient but not iNOS-deficient mice subjected to liver I/R compared to postischemic wt mice. Taken together, these data suggest that eNOS- but not iNOS-derived NO plays an important role in limiting or downregulating I/R-induced liver injury in vivo following 5 h of reperfusion.
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PMID:Nitric oxide synthase and postischemic liver injury. 1102 58

Ischemia/reperfusion contributes to the hepatic injury in resection and transplantation of the liver. However, the precise mechanisms involved in hypoxia stress remain to be clarified. Pro-inflammatory cytokines including interleukin 1beta (IL-1beta) induce a gene expression of inducible nitric oxide synthase (iNOS) and produce nitric oxide, which exerts either a cytoprotective or toxic effect. In this report, we found that hypoxia and heat markedly inhibited the induction of nitric oxide production stimulated by IL-1beta in rat cultured hepatocytes. Both treatments also abolished the induction of iNOS protein and mRNA. However, hypoxia could not prevent either degradation of an inhibitory protein (IkappaBalpha) of nuclear factor-kappaB (NF-kappaB) or translocation of NF-kappaB to the nucleus, whereas heat inhibited both of the IkappaBalpha degradation and NF-kappaB translocation. Transfection experiments with iNOS promoter construct revealed that hypoxia as well as heat significantly inhibited the transactivation of iNOS gene. Further, a hypoxia-response element located in the promoter was not involved in the inhibition of iNOS induction by hypoxia. These results indicate that hypoxia and heat suppress iNOS gene induction at the transcriptional level through different mechanisms. Reduction of nitric oxide production under hypoxic conditions may be implicated in the cellular damage or protection during hepatic ischemia/reperfusion.
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PMID:Hypoxia and heat inhibit inducible nitric oxide synthase gene expression by different mechanisms in rat hepatocytes. 1105 54

Although glial cells in the optic nerve head undergo a reactivation process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a coculture system in which retinal ganglion cells and glial cells are grown on different layers but share the same culture medium, we studied the influences of glial cells on survival of retinal ganglion cells after exposure to different stress conditions typified by simulated ischemia and elevated hydrostatic pressure. After the exposure to these stressors, we observed that glial cells secreted tumor necrosis factor-alpha (TNF-alpha) as well as other noxious agents such as nitric oxide into the coculture media and facilitated the apoptotic death of retinal ganglion cells as assessed by morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase activity. The glial origin of these noxious effects was confirmed by passive transfer experiments. Furthermore, retinal ganglion cell apoptosis was attenuated approximately 66% by a neutralizing antibody against TNF-alpha and 50% by a selective inhibitor of inducible nitric oxide synthase (1400W). Because elevated intraocular pressure and ischemia are two prominent stress factors identified in the eyes of patients with glaucoma, these findings reveal a novel glia-initiated pathogenic mechanism for retinal ganglion cell death in glaucoma. In addition, these findings suggest that the inhibition of TNF-alpha that is released by reactivated glial cells may provide a novel therapeutic target for neuroprotection in the treatment of glaucomatous optic neuropathy.
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PMID:Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. 1110 75

There is limited evidence that inhibition of the activity of the cytosolic cysteine protease calpain reduces ischemia/reperfusion injury. The multiple organ injury associated with hemorrhagic shock is due at least in part to ischemia (during hemorrhage) and reperfusion (during resuscitation) of target organs. Here we investigate the effects of calpain inhibitor I on the organ injury (kidney, liver, pancreas, lung, intestine) and dysfunction (kidney) associated with hemorrhagic shock in the anesthetized rat. Hemorrhage and resuscitation with shed blood resulted in an increase in calpain activity (heart), activation of NF-kappaB (kidney), expression of iNOS and COX-2 (kidney), and the development of multiple organ injury and dysfunction, all of which were attenuated by calpain inhibitor I (10 mg/kg i.p.), administered 30 min prior to hemorrhage. Chymostatin, a serine protease inhibitor that does not prevent the activation of NF-kappaB, had no effect on the organ injury/failure caused by hemorrhagic shock. Pretreatment (for 1 h) of murine macrophages or rat aortic smooth muscle cells (activated with endotoxin) with calpain inhibitor I attenuated the binding of activated NF-kappaB to DNA and the degradation of IkappaBalpha, IkappaBbeta, and IkappaBvarepsilon. Selective inhibition of iNOS activity with L-NIL reduced the circulatory failure and liver injury, while selective inhibition of COX-2 activity with SC58635 reduced the renal dysfunction and liver injury caused by hemorrhagic shock. Thus, we provide evidence that the mechanisms by which calpain inhibitor I reduces the circulatory failure as well as the organ injury and dysfunction in hemorrhagic shock include 1) inhibition of calpain activity, 2) inhibition of the activation of NF-kappaB and thus prevention of the expression of NFkappaB-dependent genes, 3) prevention of the expression of iNOS, and 4) prevention of the expression of COX-2. Inhibition of calpain activity may represent a novel therapeutic approach for the therapy of hemorrhagic shock.
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PMID:Calpain inhibitor I reduces the activation of nuclear factor-kappaB and organ injury/dysfunction in hemorrhagic shock. 1114 5

The phenomenon of 'ischemic preconditioning' (IP) has been vigorously investigated during the past 15 years. As our knowledge on the possible protective mechanisms of IP has been increasingly expanded, novel approaches based on preconditioning with pharmacological agents have recently emerged. Two drugs have been used to induce delayed preconditioning against myocardial infarction caused by ischemia/reperfusion. One of the drugs was monophosphoryl lipid A (MLA)--a detoxified derivative of lipopolysaccharide from gram-negative strains; and another drug was RC552--a novel synthetic glycolipid that mimics the chemical structure of MLA. We have shown that pretreatment of adult mice with MLA or RC552 (350 microg/kg) 24 h prior to the global ischemia and reperfusion in the isolated perfused heart attenuated myocardial injury. Infarct size was significantly reduced in MLA or RC552-treated groups as compared with the vehicle-treated group. The delayed cardioprotection was associated with a moderate but significant increase of nitric oxide level in the ischemic myocardium. Treatment with S-methylisothiourea (3 mg/kg), a selective inhibitor of inducible nitric oxide synthase (iNOS) abolished MLA or RC552-induced delayed protection. In addition, neither MLA nor RC552 reduced infarct size in iNOS knockout mice. Our findings suggest that both MLA and RC552 are able to induce delayed myocardial preconditioning via iNOS-dependent pathway.
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PMID:Pivotal role of nitric oxide in delayed pharmacological preconditioning against myocardial infarction. 1115 95

Cerebral ischemia is accompanied by a marked inflammatory reaction that is initiated by ischemia-induced expression of cytokines, adhesion molecules, and other inflammatory mediators, including prostanoids and nitric oxide. Preclinical studies suggest that interventions that are aimed at attenuating such inflammation reduce the progression of brain damage that occurs during the late stages of cerebral ischemia. In particular, strategies that block the activity of inflammation-related enzymes, such as inducible nitric oxide synthase and cyclo-oxygenase-2, reduce ischemic damage with an extended therapeutic window. Although a clinical trial using murine antibodies against intercellular adhesion molecule-1 did not show benefit in patients with ischemic stroke, recent data indicate that immune activation induced by the heterologous protein may have played an important role in the failure of this trial. Therefore, there is a strong rationale for continuing to explore the efficacy of anti-inflammatory therapies in the treatment of the late stages of cerebral ischemia.
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PMID:Cerebral ischemia and inflammation. 1117 23

The present study was performed to investigate whether increases in nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) were involved in impairment of learning behavior and hippocampal long-term potentiation (LTP) following transient ischemia. Rats with four-vessel occlusion (4-VO) were used as an ischemic model. One week after permanent occlusion of the vertebral arteries, the common carotid arteries were clamped for 10 min under halothane anesthesia. Aminoguanidine (10 mg/kg i.p.), a relatively selective iNOS inhibitor, or saline was administered 30 min before common carotid arteries occlusion, and every 24-h for 4 days. We investigated whether hippocampal NO production was increased by ischemic insult using microdialysis on days 1, 4 and 7 after 4-VO. On days 1 and 4 after 4-VO, increases in NO production were observed, and this effect was inhibited by aminoguanidine. Four days after 4-VO, rats were subjected to the Y-maze test and contextual fear conditioning. Ischemic insults impaired learning behavior, and aminoguanidine ameliorated the impairment induced by 4-VO. Four days after 4-VO, the changes in the population spike amplitude were recorded as an index of LTP in Schaffer collateral-CA1 (carotid artery 1), the mossy fiber-CA3 and the perforant path-dentate gyrus synapses. LTP was significantly inhibited by 4-VO, except in mossy fiber-CA3 synapses. Pretreatment with aminoguanidine prevented the reduction of LTP in perforant path-dentate gyrus, but not in Schaffer collateral-CA1 synapses. These results suggest that post-ischemic increase in NO production via iNOS impaired the learning behavior. There is an association between behavioral performance and LTP formation in perforant path-dentate gyrus synapses, but neither in Schaffer collateral-CA1 nor in mossy fiber-CA3 synapses.
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PMID:Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia. 1118 64

Hepatic blood flow decreases under cholestasis and there is evidence that NO regulates liver microvascular perfusion. Thus, the aim of the present study was to evaluate NO synthesis in cholestasis. Cholestasis was induced by bile-duct ligation (BDL) in male Wistar rats. Bilirubins and enzyme activities were measured in serum. Lipid peroxidation, GSH, GSSG and glycogen were determined in liver. Histopathological analysis was performed. Serum NO2- + NO3- concentration was measured by the Gries reaction. iNOS immunoblot analysis was carried out using an iNOS polyclonal antibody. After 7 days of BDL lipid peroxidation increased while GSH/GSSG ratio decreased. Serum NO2- + NO3- and liver iNOS protein were reduced, accompanied by ischemia as revealed by the histopathological analysis. GSH upregulates NO synthesis by increasing iNOS mRNA levels and iNOS activity, thus the reduction of GSH/GSSG ratio may be responsible for the downregulation of iNOS protein and NO synthesis, which in turn may explain the observed ischemia and the decreased hepatic blood perfusion in cholestasis reported by others.
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PMID:Nitric oxide and inducible nitric oxide synthase expression are downregulated in acute cholestasis in the rat accompanied by liver ischemia. 1124 95

Monophosphoryl Lipid A (MLA) is a detoxified derivative of endotoxin and was first derived and purified from bacterial lipopolysaccharide in 1980s. This pharmacological agent has been studied as a vaccine adjunct, anti-septic, or anti-tumor agent by means of its immunomodulatory properties. In addition, MLA is one of the most well documented protective drugs against cardiac ischemia/reperfusion injury in various animal species. Mechanisms involved with the MLA-induced cardioprotection are still not fully understood. A key role for ATP-sensitive potassium channels and inducible nitric oxide synthase (iNOS) has been proposed. This article provides a brief overview on the updated understanding of MLA-induced cardioprotection and focuses on the new evidence and insights that were brought into the field by a number of new publications during 1998-1999. Our recent study in a globally ischemic mouse heart model is particularly highlighted. An obligatory role for nitric oxide (NO) in mediating the delayed cardioprotective effect induced by MLA via induction of iNOS was double-confirmed by using S-methylisothiourea (SMT)--a specific inhibitors of iNOS as well as the iNOS gene knockout mice. A direct association of the MLA-induced infarct size reduction with increased NO production was also demonstrated in this study. Future studies should target on identifying the key type(s) of cytokine and the receptors as well as free radical-activated transcription factors that may be responsible for induction of iNOS and the subsequent anti-ischemic cardioprotection with MLA. Information gathered in the studies on MLA may eventually enhance our understanding in the mechanisms of delayed phase of myocardial preconditioning and its clinical applications.
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PMID:Nitric oxide-dependent mechanism of anti-ischemic myocardial protection induced by monophosphoryl lipid A. 1127 Sep 82

Cortical spreading depression (CSD) is characterized by reversible neuronal dysfunction in the absence of cell death. Preconditioning by CSD induces tolerance against subsequent lethal ischemia. In this study, we used quantitative reverse transcriptase-polymerase chain reaction and immunocytochemistry to analyze proinflammatory cytokine expression after CSD induced by topical application of potassium chloride (KCl) to the cortical surface of rat brains. Relative to control cortex, we found an increase of tumor necrosis factor-alpha (mean 62-fold, P < 0.001) and interleukin (IL)-1beta (mean 24-fold, P < 0.001) mRNA levels within 4 hours ipsilateral to the site of KCl application. At 16 hours cytokine expression was decreasing toward baseline levels. Ipsilateral cytokine induction was abolished by pretreatment with the noncompetitive N-methyl-d-aspartate antagonist, MK-801. In contrast to focal cortical infarction, cytokine induction in CSD was not accompanied by the expression of inducible nitric oxide synthase mRNA. In immunocytochemical studies, expression of IL-1beta protein was localized to ramified microglia in cortical layers I to III of the ipsilateral hemisphere. Our finding that NMDA receptor signaling without subsequent neuronal cell death is sufficient to induce inflammatory cytokine expression in the brain has basic implications for central nervous system immunoregulation. We postulate that cytokine expression in CSD forms part of a physiologic stress response that contributes to the development of ischemic tolerance in this and other preconditioning paradigms.
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PMID:Cortical spreading depression induces proinflammatory cytokine gene expression in the rat brain. 1129 76


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