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)

In the brain large amounts of nitric oxide are produced in response to various pathological stimuli such as infectious agents, ischemia and trauma. Although it is known that endothelial cells can express the inducible isoform of nitric oxide synthase (iNOS) upon activation, the impact of different cytokines on iNOS expression in rat microvascular endothelial cells remains unclear. We now investigated iNOS mRNA expression and enzyme activity in primary cell cultures of rat microvascular brain endothelial cells after treatment with the proinflammatory cytokines interleukin-1beta (IL-1beta), Tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) alone or in combination. Cells were characterized by immunocytochemistry staining for von-Willebrand-factor and the rat brain endothelial antigen recognized by monoclonal antibody Ox2. iNOS-enzyme activity was determined by measurement of nitrite in the supernatants of cell culture using the Griess-reaction. In addition mRNA expression was analysed by RT-PCR with iNOS and IL-1beta specific primers. All cells in the endothelial cell culture were found to express the antigenic phenotype vWF+/Ox2+/Ox43-, thus identifying the cells as rat brain endothelial cells of microvascular origin. IL-1beta was the only cytokine that as a single stimulus induced iNOS mRNA expression and iNOS-enzyme activity in these endothelial cells. All combinations of two cytokines, including that of TNF-alpha and IFN-gamma--or the triple combination led to expression of iNOS-mRNA and active protein. Cell activation by the combination of TNF-alpha + IFN-gamma led to an early expression of IL-1beta by the endothelial cells suggesting iNOS induction as a consequence of endogenous IL-1beta production under this challenge. The experiments prove that rat brain microvascular endothelial cells express iNOS and produce large amounts of NO under inflammatory conditions. Furthermore, our results indicate a decisive role of IL-1beta in iNOS expression and NO generation.
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PMID:The dominant role of exogenous or endogenous interleukin-1 beta on expression and activity of inducible nitric oxide synthase in rat microvascular brain endothelial cells. 925 76

Tumor necrosis factor-alpha (TNF alpha) is a cytokine rapidly produced in the brain in response to vigorous neuronal activity and tissue injury. TNF alpha may protect neurons against excitotoxic and oxidative insults by a mechanism involving activation of the transcription factor NF-kappaB. Whole-cell perforated patch clamp recordings in cultured rat hippocampal neurons showed that long-term treatment (24-48 h) with TNF alpha increases Ca2+ current density; pharmacological analysis indicated a major increase in current through L-type voltage-dependent calcium channels. Long-term treatment with TNF alpha caused a decrease in currents induced by glutamate, NMDA, AMPA, and kainate. Shorter exposures to TNF alpha (acute; 2 h) did not alter Ca2+ current or glutamate receptor agonist-induced currents. Ceramide, an intracellular messenger that activates the transcription factor NF-kappaB, mimicked the actions of TNFs on Ca2+ current density and currents induced by glutamate receptor agonists. Cotreatment with kappaB decoy DNA abolished the effects of TNF alpha on Ca2+ current and excitatory amino acid-induced currents, demonstrating a requirement for NF-kappaB activation in the actions of TNF alpha. Neurons pretreated with TNF alpha exhibited increased intracellular Ca2+ concentrations following membrane depolarization but reduced intracellular Ca2+ concentration responses to excitatory amino acids, compared with neurons in untreated control cultures or cultures cotreated with kappaB decoy DNA. These findings suggest important roles for the transcription factor NF-kappaB in modulation of voltage-dependent calcium channels and glutamate receptors and the many physiological and pathophysiological processes in which these ion channels are involved. Such signaling mechanisms may be particularly important in injury settings such as ischemia or trauma, where TNF alpha expression is increased and NF-kappaB is activated.
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PMID:The transcription factor NF-kappaB mediates increases in calcium currents and decreases in NMDA- and AMPA/kainate-induced currents induced by tumor necrosis factor-alpha in hippocampal neurons. 957 71

A total of 12 mongrel dogs were divided into two equal groups. Six animals received IIoprost and the other 6 animals did not receive any additional treatment. In the Iloprost group, Iloprost was added to the cardioplegic solution (25 ng). Also, Iloprost was used (10 ng/kg/min.) 5 min. before and after cross-clamping. All cardiac output and biochemical measurements were evaluated before cross-clamp and 15 min., 1 h, and 4 h after cross-clamp. The measured dp/dt shows that the hearts treated with Iloprost preserved left ventricular function. Comparison of contractility indices between the groups revealed that contractile recovery was 59% in the control group and 71% in the Iloprost group (p < 0.05). Tumor necrosis factor (TNF) alpha level was significantly elevated in the control group (p < 0.001). Its level was 22.2 +/- 2.2 pg/mL in the control group and 13.8 +/- 1.0 pg/mL in the Iloprost group. E- and P-selectin levels were elevated in the control group (p < 0.001). ICAM-1 level was also elevated in the control group. ICAM-1 level was 17.7 +/- 1.8 ng/mL in the control group and 8.5 +/- 1.8 ng/mL in the Iloprost group. The Iloprost that was added to the cardioplegic solution and low dose administration during the pre- and post-ischemic period inhibits the toxic mediator release from endothelium-leukocyte interaction and reduces the severity of ischemia-reperfusion injury.
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PMID:Iloprost added to the cardioplegic solutions improves myocardial performance. 966 Dec 18

Tumor necrosis factor (TNF) is released during hepatic ischemia/reperfusion (I/R) and plays an important role in the ensuing neutrophil-mediated lung and liver injury. Since TNF is not a direct neutrophil chemotaxin, we hypothesized that TNF may up-regulate neutrophil adhesion molecules, specifically intercellular adhesion molecule-1 (ICAM-1), following hepatic I/R, and that this molecule then plays an important role in tissue neutrophil influx. Rats underwent 90 min of lobar hepatic ischemia with reperfusion. Pulmonary and hepatic ICAM-1 expression were assessed by reverse transcription-polymerase chain reaction, Western blot analysis, and immunohistochemical staining. Increases in hepatic ICAM-1 were demonstrated within 1 h of reperfusion, while increases in pulmonary ICAM-1 were not seen until 6 h of reperfusion. Next, rats were treated with anti-TNF antibody or control antibody without TNF neutralizing properties prior to hepatic I/R. Pretreatment with anti-TNF antibody significantly decreased pulmonary and hepatic ICAM-1 expression after hepatic I/R. We next investigated the effects of pretreatment with anti-ICAM-1 antibodies on the lung and liver injury that follows hepatic I/R. Lung injury was assessed by changes in pulmonary capillary permeability as estimated by extravasation of Evans Blue dye and pulmonary neutrophil influx as measured by lung myeloperoxidase levels. Liver injury was assessed by hepatic neutrophil morphometrics and plasma liver enzymes (alanine aminotransferase). Pretreatment with anti-ICAM-1 antibodies significantly decreased pulmonary capillary permeability, pulmonary myeloperoxidase, hepatic neutrophil influx, and plasma alanine aminotransferase, as compared to animals pretreated with control antibody. These data suggest that TNF is a proximal trigger for pulmonary and hepatic ICAM-1 up-regulation following hepatic ischemia with reperfusion, and that ICAM-1 is important for pulmonary and hepatic neutrophil influx, with the resultant tissue injury, following hepatic I/R.
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PMID:Tumor necrosis factor up-regulates intercellular adhesion molecule 1, which is important in the neutrophil-dependent lung and liver injury associated with hepatic ischemia and reperfusion in the rat. 974 46

Recent evidence indicates that thrombolysis may be an effective therapy for the treatment of acute ischemic stroke. However, the reperfusion of ischemic brain comes with a price. In clinical trials, patients treated with thrombolytic therapy have shown a 6% rate of intracerebral hemorrhage, which was balanced against a 30% improvement in functional outcome over controls. Destruction of the microvasculature and extension of the infarct area occur after cerebral reperfusion. We have reviewed the existing data indicating that an inflammatory response occurring after the reestablishment of circulation has a causative role in this reperfusion injury. The recruitment of neutrophils to the area of ischemia, the first step to inflammation, involves the coordinated appearance of multiple proteins. Intercellular adhesion molecule-1 and integrins are adhesion molecules that are up-regulated in endothelial cells and leukocytes. Tumor necrosis factor-alpha, interleukin-1, and platelet-activating factor also participate in leukocyte accumulation and subsequent activation. Therapies that interfere with the functions of these factors have shown promise in reducing reperfusion injury and infarct extension in the experimental setting. They may prove to be useful adjuncts to thrombolytic therapy in the treatment of acute ischemic stroke.
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PMID:Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. 984 53

Tumor necrosis factor-alpha (TNF-alpha) is a key mediator of shock-induced cellular and humoral inflammatory cascades. The present study investigated the role of TNF-alpha in oxidative membrane injury and altered hepatocyte Ca2+ regulation, both of which are critical steps in cellular dysfunction during ischemia/reperfusion events. Hemorrhagic shock was induced by bleeding male Sprague-Dawley rats (200-250 g, n=6/group) to a mean arterial blood pressure of 40 mmHg for 60 min. Rats were resuscitated with 60% of shed blood and twice the shed blood volume as Ringers' lactate. At the end of hemorrhage and 60 min after resuscitation, hepatocytes were isolated by liver collagenase perfusion. Hepatocyte Ca2+ uptake (Ca2+up) and Ca2+ membrane flux (Ca2+flux) were determined by 45Ca2+ incubation techniques. Hepatocyte reduced/oxidized glutathione and lipid peroxidation were determined fluorometrically. Both hemorrhage and hemorrhage/resuscitation significantly increased hepatocyte Ca2+up and Ca2+flux. The monoclonal chimeric mouse gamma1 TNF-alpha antibody (TN3gamma1.19.12; 20 mg/kg b.w.) given with resuscitation significantly decreased hepatocyte Ca2+up and Ca2+flux and prevented hepatocyte lipid peroxidation. These findings suggest that oxidative membrane injury could be the result of TNF-alpha modulation of hepatocellular Ca2+ regulation during hemorrhage/resuscitation.
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PMID:Monoclonal antibody to tumor necrosis factor-alpha modulates hepatocellular Ca2+ homeostasis during hemorrhagic shock in the rat. 993 Sep 19

Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory mediator of the immune response to allogenic and infectious stimuli. Non-immunosuppressed individuals possessing a NcoI restriction enzyme site in the TNF gene locus produce less TNF-alpha in vitro and in vivo compared with individuals lacking this restriction site. We performed polymerase chain reaction amplification and restriction enzyme fragment length analysis of the TNF locus from 86 liver transplant recipients to determine if presence of the NcoI site is associated with the frequency of rejection or infection, time to rejection or infection, and patient and graft survival. We controlled for recipient primary diagnosis, age, sex, United Network for Organ Sharing status, year of transplant, type of immunosuppression, use of anti-lymphocyte agents, and graft ischemia time. Fifty-six recipients possessed the NcoI+/low TNF-alpha genotype and 30 were NcoI-/high TNF-alpha genotype. In the first year after transplant, there were no significant differences in the frequency, or time to first rejections or the overall number of rejection episodes between the two genotypes. NcoI+/low TNF-alpha genotype recipients had significantly more infections (1.52 vs. 0.87, P=0.014). In a linear regression, multivariate model controlling for all marginally significant variables, the NcoI+/low TNF-alpha genotype was still associated with significantly more infections (P=0.0031). Patient and graft survival were equal for the two groups. One implication of this study, in individuals genetically predetermined to be low TNF-alpha producers, is that additional inhibition of TNF-alpha production by routine immunosuppression may be excessive, rendering these individuals less able to respond to infectious stimuli. These patients may benefit from lower doses or withdrawal of corticosteroids.
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PMID:Tumor necrosis factor genetic polymorphisms correlate with infections after liver transplantation. NEMC TNF Study Group. New England Medical Center Tumor Necrosis Factor. 1022 85

Recent evidence has implicated proinflammatory mediators such as TNF-alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Both cardiopulmonary bypass and renal ischemia-reperfusion injury induce a cascade of events leading to cellular damage and organ dysfunction. Tumor necrosis factor (TNF), a potent proinflammatory cytokine, is released from both the heart and the kidney in response to ischemia and reperfusion. TNF released during cardiopulmonary bypass induces glomerular fibrin deposition, cellular infiltration, and vasoconstriction, leading to a reduction in glomerular filtration rate (GFR). The signaling cascade through which renal ischemia-reperfusion induces TNF production is beginning to be elucidated. Oxidants released following reperfusion activate p38 mitogen-activated protein kinase (p38 MAP kinase) and the TNF transcription factor, NFkappaB, leading to subsequent TNF synthesis. In a positive feedback, proinflammatory fashion, binding of TNF to specific TNF membrane receptors can reactivate NFkappaB. This provides a mechanism by which TNF can upregulate its own expression as well as facilitate the expression of other genes pivotal to the inflammatory response. Following its production and release, TNF results in both renal and myocardial apoptosis and dysfunction. An understanding of these mechanisms may allow the adjuvant use of anti-TNF therapeutic strategies in the treatment of renal injury. The purposes of this review are: (1) to evaluate the evidence which indicates that TNF is produced by the heart following cardiopulmonary bypass; (2) to examine the effect of TNF on myocardial performance; (3) to outline the mechanisms by which the kidney produces significant TNF in response to ischemia and reperfusion; (5) to investigate the role of TNF in renal ischemia-reperfusion injury, (6) to describe the mechanisms of TNF-induced renal cell apoptosis, and (7) to suggest potential anti-TNF strategies designed to reduce renal insufficiency following cardiac surgery.
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PMID:Role of TNF in mediating renal insufficiency following cardiac surgery: evidence of a postbypass cardiorenal syndrome. 1042 18

Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3-(4-morpholinyl)-sydnonimine (0.01-1 mM/L). Intercellular adhesion molecule 1 surface expression was measured in a cell surface enzyme-linked immunosorbent assay, intercellular adhesion molecule 1 mRNA by Northern analysis. Human saphenous vein endothelial cells were transfected with the inducible nitric oxide synthase gene and stimulated with tumor necrosis factor alpha (300 U/mL). Fluorescein green-labeled polymorphonuclear leukocytes adhering to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells were quantified by epifluorescent microscopy. The intercellular adhesion molecule 1 surface expression of activated human umbilical vein endothelial cells/human saphenous vein endothelial cells was significantly diminished to 40 to 60% of the maximum after treatment with CAS 1609, 3-(4-morpholinyl)-sydnonimine, or transfection with the inducible nitric oxide synthase gene. Intercellular adhesion molecule 1 mRNA was diminished by CAS 1609 and 3-(4-morpholinyl)-sydnonimine in the same manner. The functional relevance of our data was shown by reduction of polymorphonuclear leukocyte adherence to activated human umbilical vein endothelial cells/human saphenous vein endothelial cells following treatment with CAS 1609 and 3-(4-morpholinyl)-sydnonimine or transfection with inducible nitric oxide synthase. Tumor necrosis factor-induced polymorphonuclear leukocyte adherence was abolished by blocking antibody against intercellular adhesion molecule 1. Thus, exogenous or endogenous substitution of nitric oxide diminishes the expression of endothelial intercellular adhesion molecule 1 and its mRNA following tumor necrosis factor alpha stimulation. This results in a reduced polymorphonuclear leukocyte adherence to activated endothelium.
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PMID:NO reduces PMN adhesion to human vascular endothelial cells due to downregulation of ICAM-1 mRNA and surface expression. 1068 Jun 42

Tumor necrosis factor-alpha (TNF-alpha) level, tissue-typed plasminogen activator(t-PA) activity and PA inhibitor (PAI) activity were determined in three groups: (1) 25 NIDDM patients with silent myocardial ischemia (SMI) or silent cerebral ischemia (SCI); (2) 18NIDDM patients without SMI or SCI; (3) 20 age-matched normal controls. Diagnosis of SMI or SCI was based on the finding of ischemic evidence by SPECT of myocardiotomograph or cerebrotomograph. All patients ECG and blood pressure were normal, and they had no history of clinical symptoms and signs of MI or CI. The result showed that the TNF-alpha level and PAI activity in the ischemia group were the highest and the t-PA activity in the ischemia group was the lowest, as compared with those in the other two groups respectively. It suggests that in NIDDM patients who have high TNF-alpha, high PAI activity, low t-PA, and even no symptoms and signs of MI or CI, anticoagulant therapy might be useful to prevent the progression of diabetic macroangiopathies.
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PMID:[Changes of serum TNF-alpha level, t-PA activivty and PAI activity in patients with silent myocardial ischemia or silent cerebral ischemia]. 1068 70


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