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)

Proinflammatory mediators such as tumor necrosis factor-alpha (TNF) have been implicated in the pathophysiology in a number of acute disease states. Tumor necrosis factor-alpha can contribute to cell death, apoptosis, and organ dysfunction. Tumor necrosis factor-alpha can be generated with sepsis or ischemia-reperfusion by activation of cell mitogen-activated protein kinases and nuclear factor kappa B, leading to TNF production. A number of strategies to modulate TNF have been recently explored, including factors directed toward mitogen-activated protein kinases, TNF transcription, anti-inflammatory ligands, heat shock proteins, and TNF-binding proteins. However, TNF may also play an important role in the adaptive response to injury and inflammation. Control of the deleterious effects of TNF and other proinflammatory cytokines represents a realistic goal for clinical emergency medicine. The purpose of this article is to provide a background of relevance to emergency medicine academicians on the production and regulation of TNF, the acute effects of TNF on pathophysiology, and the rationale for therapeutic interventions directed toward TNF and the clinical experience with these strategies.
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PMID:Bench to bedside: tumor necrosis factor-alpha: from inflammation to resuscitation. 1095 39

Although tumor necrosis factor-alpha has been implicated in liver injury after both warm ischemia- and cold ischemia-reperfusion, it is unclear whether reactivity of the liver to these stimuli is similar with regard to cytokine expression. Here we compare the effects of warm and cold ischemia on tumor necrosis factor-alpha expression and test the hypothesis that cold ischemia preceding warm ischemia causes overexpression of this cytokine. Rat livers were flushed out with University of Wisconsin solution and subjected to varying periods of warm ischemia, cold ischemia, or cold ischemia plus warm ischemia followed by reperfusion using a blood-free perfusion model. Tumor necrosis factor-alpha and interleukin-10 release into the perfusate and bile were measured by ELISA, and expression of these cytokines and that of c-fos, c-jun, and c-myc were studied by reverse-transcriptase polymerase chain reaction. We found high levels of tumor necrosis factor-alpha in the perfusates of livers subjected to warm ischemia-reperfusion, whereas minimal or no tumor necrosis factor-alpha was detected in livers subjected to cold ischemia-reperfusion or to cold ischemia plus warm ischemia-reperfusion. Reverse-transcriptase polymerase chain reaction confirmed the above findings and showed that immediate early genes were expressed in reperfused groups of livers. Measurements of cytokine release into bile showed that neither tumor necrosis factor-alpha nor interleukin-10 were upregulated by cold ischemia-reperfusion. The results suggest that (1) warm ischemia- and cold ischemia-reperfusion of rat liver lead to very different outcomes with regard to tumor necrosis factor-alpha expression and (2) cold ischemia preceding warm ischemia prevents upregulation of tumor necrosis factor-alpha.
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PMID:Marked difference in tumor necrosis factor-alpha expression in warm ischemia- and cold ischemia-reperfusion of the rat liver. 1122 27

Tumor necrosis factor (TNF) is an important factor in various acute and chronic neurodegenerative disorders. In retinal ischemia, we show early, transient upregulation of TNF, TNF receptor 1 (TNF-R1), and TNF-R2 6 hr after reperfusion preceding neuronal cell loss. To assess the specific role of TNF and its receptors, we compared ischemia-reperfusion-induced retinal damage in mice deficient for TNF-R1, TNF-R2, or TNF by quantifying neuronal cell loss 8 d after the insult. Surprisingly, TNF deficiency did not affect overall cell loss, yet absence of TNF-R1 led to a strong reduction of neurodegeneration and lack of TNF-R2 led to an enhancement of neurodegeneration, indicative of TNF-independent and TNF-dependent processes in the retina, with TNF-R1 augmenting neuronal death and TNF-R2 promoting neuroprotection. Western blot analyses of retinas revealed that reduction of neuronal cell loss in TNF-R1/ animals correlated with the presence of activated Akt/protein kinase B (PKB). Inhibition of the phosphatidylinositol 3-kinase signaling pathway reverted neuroprotection in TNF-R1-deficient mice, indicating an instrumental role of Akt/PKB in neuroprotection and TNF-R2 dependence of this pathway. Selective inhibition of TNF-R1 function may represent a new approach to reduce ischemia-induced neuronal damage, being potentially superior to strategies aimed at suppression of TNF activity in general.
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PMID:Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. 1191

Tumor necrosis factor-alpha (TNF-alpha) depresses myocardial contractility, and overexpression of TNF-alpha in the myocardium contributes to cardiac dysfunction caused by both systemic and local insults. Sepsis, endotoxemia, hemorrhagic shock, and myocardial ischemia-reperfusion all promote cardiac dysfunction in part by a TNF-alpha-mediated mechanism. Thus, TNF-alpha represents an appealing therapeutic target for myocardial protection against multiple clinically relevant insults. The inducible 70-kD heat shock protein (Hsp70) is expressed in the myocardium in response to stress and has been linked to enhanced myocardial resistance to depression associated with ischemia-reperfusion or sepsis. The mechanism by which Hsp70 protects cardiac function against a subsequent insult remains obscure. In vitro induction of Hsp70 in monocytes or macrophages inhibits TNF-alpha production following bacterial lipopolysaccharide stimulation, and in vivo induction of Hsp70 down-regulates tissue TNF-alpha production following an injurious insult. Understanding of the regulatory role of Hsp70 in the myocardial inflammatory response will provide insights into the mechanism by which Hsp70 preserves cardiac function and may yield therapies for protection of the myocardium against depression associated injurious insults.
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PMID:The interaction between Hsp70 and TNF-alpha expression: a novel mechanism for protection of the myocardium against post-injury depression. 1202 52

Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines, some of which are regulated by the nuclear transcription factor NF-kappaB. In this study the authors examined mRNA expression levels for several important genes associated with inflammation at five time points (3, 6, 12, 24, and 72 hours) after transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. A sensitive and quantitative technique (TaqMan real-time QRT-PCR) was used to simultaneously measure mRNA levels for key cell adhesion molecules and inflammatory cytokines. Gene expression increased significantly in the injured hemisphere for interleukin (IL)-1beta (12-fold increase at 24 hours), IL-6 (25-fold increase at 6 hours) and ICAM-1 (4-fold increase at 24 hours), and the interhemispheric differences for these genes were significant for every time point examined (P < 0.05 for all values). Tumor necrosis factor-alpha mRNA was upregulated in the injured versus uninjured hemisphere from 3 to 24 hours (5-fold increase at 6 hours), while E-selectin showed a significant increase in mRNA levels from 6 to 24 hours after MCAO (10-fold increase at 6 hours) (P < 0.05 for all values). VCAM-1 mRNA levels did not respond differentially to injury at any time point between the two brain hemispheres. At all time points examined, activated NF-kappaB immunoreactivity was observed in cells throughout the infarct-damaged tissue. These results are consistent with the proinflammatory properties of the induced molecules, which are involved in the initiation of the inflammatory cascade, and may thus contribute to secondary cellular responses that lead to further brain damage.
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PMID:Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. 1221 12

Ischemia/reperfusion injuries are a major problem in liver resections and transplantations. Tumor necrosis factor-alpha has been widely investigated as a key mediator in the mechanism of ischemia/reperfusion injury. Upstream signal transduction mechanisms for tumor necrosis factor-alpha have not been well documented. Therefore, we assessed c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model. Male Wistar rats were subjected to 30 minutes of ischemia followed by reperfusion. Hepatic enzymes, histological examinations, microfluorographs, and tumor necrosis factor-alpha protein production (in the serum and liver tissue) were analyzed during the course of reperfusion. c-Jun N-terminal kinase activity was measured by a radioisotope kinase assay. Ischemia/reperfusion injuries were characterized by an elevation in hepatic enzyme, the histological degeneration of hepatocytes, and an increase in the number of nonviable cells. Moreover, increased endothelial-adherent leukocytes and tumor necrosis factor-alpha protein production were also observed. c-Jun N-terminal kinase activity at 60 minutes after reperfusion was 12.4 times higher than the pre-ischemia level. These results suggest that c-Jun N-terminal kinase may play some role in the mechanism of ischemia/reperfusion injuries.
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PMID:c-Jun N-terminal kinase activation during warm hepatic ischemia/reperfusion injuries in a rat model. 1240 68

Tumor necrosis factor (TNF) alpha is a critical mediator of inflammation; however, TNFalpha is rarely released alone and the "cross-talk" between different classes of inflammatory mediators is largely unexplored. Thromboxane A(2) (TXA(2)) is released during I/R injury and exerts its effects via a G protein-linked receptor (TP). In this study, we found that TXA(2) mimetics stimulate leukocyte adhesion molecule (LAM) expression on endothelium via TPbeta. The potential interaction between TXA(2) and TNFalpha in altering endothelial survival and LAM expression was examined. IBOP, a TXA(2) mimetic, attenuated TNFalpha-induced LAM expression in vitro, in a concentration-dependent manner, by preventing TNFalpha-enhanced gene expression, and also reduced TNFalpha-induced leukocyte adhesion to endothelium both in vitro and in vivo. IBOP abrogated TNFalpha-induced NFkappaB activation in endothelial cells, as determined by reduced IkappaB phosphorylation and NFkappaB nuclear translocation, by inhibiting the assembly of signaling intermediates with the intracellular domain of TNF receptors 1 and 2 in response to TNFalpha. This inhibition resulted from the Galpha(q)-mediated enhancement of STAT1 activation and was reversed by anti-STAT1 antisense oligonucleotides. TNFalpha-mediated TNFR1-FADD association and caspase 8 activation were not inhibited by IBOP co-stimulation, however, resulting in a 2.6-fold increase in endothelial cell apoptosis. By stimulating the vessel wall and inducing endothelial cell apoptosis, TXA(2), in combination with TNFalpha, may hamper the angiogenic response during inflammation or ischemia, thus reducing revascularization and tissue viability.
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PMID:Inhibition of tumor necrosis factor alpha-mediated NFkappaB activation and leukocyte adhesion, with enhanced endothelial apoptosis, by G protein-linked receptor (TP) ligands. 1251 20

Ischemia/reperfusion injury involves a large number of humoral and cellular mediators that activate leukocytes that subsequently migrate to local tissues. Tumor necrosis factor (TNF)-alpha may be one of the most important mediators of this post-shock inflammatory response. In this study, we investigated the influence of a recombinant Type I (55 kDa) TNF-binding protein (TNF-BP) on leukocyte-endothelial interactions in the liver after hemorrhagic shock. Hemorrhagic shock was induced in female Sprague-Dawley rats (40 mmHg for 90 min) and a standardized resuscitation regimen was applied. At the time of resuscitation, animals were treated intravenously with either TNF-BP 4 mg/kg or placebo. The liver microcirculation was investigated using intravital fluorescence microscopy and immunohistochemistry at 5 h and 48 h after reperfusion. At 5 h, treatment with TNF-BP significantly reduced temporary leukocyte adhesion in the liver sinusoids as well as mean adhesion time of leukocytes in the hepatic central vein. In contrast, after 48 h, permanent leukocyte adhesion in the central hepatic vein was significantly reduced in the group receiving TNF-BP, whereas temporary leukocyte adhesion and mean adhesion time did not differ between the two groups. Both types of leukocyte adhesion, rolling adhesion after 5 h and firm adhesion after 48 h, were reduced in the group treated with TNF-BP, thereby suggesting a long-lasting anti-inflammatory effect.
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PMID:Attenuation of leukocyte adhesion by recombinant TNF-binding protein after hemorrhagic shock in the rat. 1274 90

Tumor necrosis factor (TNF)-alpha overexpression has been related to experimental ischemic tolerance when transient ischemia precedes cerebral infarction. We investigated TNF-alpha and interleukin (IL)-6 plasma concentrations in 283 patients with an acute stroke within 24 hours after symptom onset. An ipsilateral transient ischemic attack (TIA) within 72 hours before stroke was recorded in 38 patients. The infarct volume measured on computed tomography on days 4 to 7 and the frequency of poor outcome (Barthel Index score < 85) at 3 months were significantly lower in patients with prior TIA. Plasma concentrations of TNF-alpha were higher (42.5 +/- 9.9 vs 13.1 +/- 6.4pg/ml, p < 0.0001) and IL-6 levels were lower (10.1 +/- 6.2 vs 28.3 +/- 17.3pg/ml, p < 0.0001) in patients with prior TIA. A new variable termed TNF-alpha/IL-6 index was considered positive when TNF-alpha was greater than 30pg/ml and IL-6 was less than 30pg/ml. Positive TNF-alpha/IL-6 index was found in 92% of patients with prior TIA and in 1% of those without. TNF-alpha/IL-6 index (p = 0.0003) and TIA (p = 0.0001) were associated with good outcome in logistic regression analysis after adjusting for potential confounding factors. Ischemic tolerance in acute stroke is associated with increased plasma levels of TNF-alpha in the presence of reduced concentrations of IL-6.
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PMID:The release of tumor necrosis factor-alpha is associated with ischemic tolerance in human stroke. 1468 91

Tumor necrosis factor alpha (TNFalpha) is an immunomodulatory and proinflammatory cytokine implicated in neuroinflammation and neuronal damage in response to cerebral ischemia. Tumor necrosis factor-alpha converting enzyme (TACE or ADAM17) is a key sheddase that releases TNFalpha from its inactive cell-bound precursor. Using a selective small molecule inhibitor of TACE, DPH-067517, we tested the hypothesis that inhibition of TNFalpha formation might have a salutary effect in ischemic stroke induced by embolic occlusion of the middle cerebral artery (MCAO). DPH-067517 selectively inhibited TACE enzyme activity in vitro (K(i) = 2.8 nM), and effectively suppressed ischemia-induced increase in soluble TNFalpha in brain tissue after systemic administration. DPH-067517 (3 and 30 mg/kg, i.p. administered 15 min before MCAO) produced 43% (n = 8, p = 0.16) and 58% (n = 8, p < 0.05) reduction in infarct size and 36% (p < 0.05) and 23% (p < 0.05) reduction in neurological deficits, respectively. The salutary effect of DPH-067517 in ischemic brain injury was also observed when the first dose was administrated 60 min after the onset of ischemia. Inhibition of TACE had no effect on apoptosis measured by levels of active caspase-3 expression and DNA fragmentation. Our data suggest that inhibition of TACE might be a potential therapeutic strategy for neuroprotection after focal ischemic stroke.
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PMID:Inhibition of tumor necrosis factor-alpha-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. 1504 18


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