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)

Recent studies have shown that heart diseases are always accompanied with high levels of IL-1beta and a decrease in Na+-K+ ATPase concentrations. This work studies the involvement of the cytokine in the observed changes in the pump. Rats were injected intraperitoneally with 400 mg of IL-1beta and 4 h later, the heart was isolated and a crude homogenate of the right and left ventricles was prepared and tested for Na+-K+ ATPase activity and protein expression. IL-1beta inhibited by around 70% the activity of the ATPase in the left and right ventricles. This inhibition of the pump was ascribed to a decrease in its protein expression as demonstrated by western blot analysis. A dose and time response study conducted on isolated cardiac myocytes confirmed the inhibitory role of the cytokine on the ATPase and showed that IL-1beta exerts its maximal down-regulatory effect at 2 h and at a dose of 20 ng/ml. The cytokine caused also an up-regulation of the NaKCl2 cotransporter. Both MEK and p38MAPK were shown to be involved in the signaling pathway activated by the cytokine. It can be concluded that the decrease in the Na+-K+ ATPase concentration observed in heart diseases is a consequence of the accompanying high levels of IL-1beta, and may be responsible for the different symptoms that accompany cardiac ischemia.
Cytokine 2004 Apr 07
PMID:Interleukin-1 beta inhibits Na+-K+ ATPase activity and protein expression in cardiac myocytes. 1501 5

Humans exhibit substantial inter-individual differences in TNF-alpha production upon endotoxin stimulation. To determine to what extent the lipopolysaccharide-induced TNF-alpha production capacity in vivo and ex vivo is determined by polymorphisms in toll-like receptor-4 (TLR4), the TNF-alpha promoter region and Nod2, we screened for two TLR4 polymorphisms, a Nod2 polymorphism and the TNF-alpha promoter polymorphisms. We measured the perioperative endotoxemia and TNF-alpha production and the TNF-alpha production capacity of each patient in a whole-blood stimulation assay using blood drawn before anesthesia, using various LPS concentrations, in patients undergoing elective cardiac surgery. This operation represents a major surgical trauma associated with ischemia-reperfusion injury and triggers an endotoxemia and profound inflammatory response. In vivo TNF-alpha production was positively correlated with the level of endotoxemia after aortic declamping; thus TNF-alpha levels were higher in patients having endotoxemia compared to patients without endotoxemia. This correlation was observed in patients with any of the genotypes studied, and did not differ between the various genotypes. In vivo TNF-alpha levels correlated best with those ex vivo after stimulation with 1000 ng/mL LPS, and the estimated maximal TNF-alpha release capacity. Subjects with the wild-type TLR4 gene had similar levels of TNF-alpha upon LPS stimulation ex vivo as compared with patients carrying Asp299Gly and/or the Thr399Ile TLR4 polymorphism. Our results indicate that polymorphisms in the TLR4 receptor, Nod2 and TNF-alpha promoter region are not strongly associated with in vivo and ex vivo TNF-alpha production capacity upon endotoxin stimulation. This suggests that in this model of natural LPS release, the variation between individuals in TNF-alpha release can only modestly be determined by genetic background (TNF-alpha promoter, Nod2 and TLR4) of the individual.
Cytokine 2004 Apr 07
PMID:TNF-alpha promoter, Nod2 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. 1501 7

Preservation of endothelial functions with low-dose nitric oxide (NO) and inhibition of excessive production of NO from inducible NO synthase (iNOS) is a potential therapeutic approach for acute stroke. Based on this hypothesis, an NO modulator, S-nitrosoglutathione (GSNO) was used, which provided neuroprotection in a rat model of focal cerebral ischemia. Administration of GSNO after the onset of ischemia reduced infarction and improved cerebral blood flow. To understand the mechanism of protection, the involvement of inflammation in ischemic brain injury was examined. Treatment with GSNO reduced the expression of tumor necrosis factor-alpha, interleukin-1beta, and iNOS; inhibited the activation of microglia/macrophage (ED1, CD11-b); and downregulated the expression of leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 in the ischemic brain. The number of apoptotic cells (including neurons) and the activity of caspase-3 were also decreased after GSNO treatment. Further, the antiinflammatory effect of GSNO on expression of iNOS and activation of NF-kappaB machinery in rat primary astrocytes and in the murine microglial cell line BV2 was tested. Cytokine-mediated expression of iNOS and activation of NF-kappaB were inhibited by GSNO treatment. That GSNO protects the brain against ischemia/reperfusion injury by modulating NO systems, resulting in a reduction in inflammation and neuronal cell death was documented by the results.
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PMID:S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. 1564 46

To determine to what extent lipopolysaccharide-induced IL-10 production capacity is determined by polymorphisms in toll-like receptor-4 (TLR4) and the IL-10 promoter region, we measured in vivo IL-10 and TNF-alpha production in patients undergoing elective cardiopulmonary bypass surgery, a major surgical trauma associated with ischemia-reperfusion injury that triggers an endotoxemia and profound inflammatory response in most patients. Ex vivo the IL-10 and TNF-alpha production was measured in a whole blood stimulation assay, using 3 LPS concentrations. Positive correlations were found between TNF-alpha and IL-10 production ex vivo, upon stimulation with each of the LPS concentrations. Also, the estimated TNF-alpha and IL-10 EC50, and TNF-alpha(max) and IL-10max were positively correlated (r = 0.203; p = 0.023 and r = 0.287; p = 0.001, respectively), indicating that these parameters describing LPS sensitivity and maximal production capacity, respectively, can be estimated by measuring either TNF-alpha or IL-10. Interleukin-10 concentrations in patients experiencing endotoxemia in vivo negatively correlated with the IL-10 levels produced upon stimulation with 1000 ng/mL LPS as well as the estimated IL-10max ex vivo. In vivo, a positive correlation between the TNF-alpha concentration at time-point 2 and the IL-10 concentration at time-point 3 was found, consistent with an important contribution of the magnitude of TNF-alpha release upon the subsequent IL-10 production. Carriers of the IL-10 promoter -1330G, -1082A, -819T, -592A (GATA) haplotype had lower IL-10 production ex vivo upon stimulation with 10 and 100 ng/mL LPS and higher EC50 values (the estimated LPS concentration at which 50% of the maximal IL-10 response is reached) as compared to carriers of the other haplotypes combined, indicating decreased LPS sensitivity ex vivo. These individuals did not differ from the others in interleukin-10 production capacity upon stimulation with a high LPS concentration (i.e., 1000 ng/mL) and the estimated IL-10(max) values, were similar, indicating unimpaired maximal IL-10 production capacity ex vivo. Carriers of the IL-10 promoter AGCC haplotype had lower EC50 values as compared to carriers of the other haplotypes combined, indicating increased LPS sensitivity ex vivo. In accordance with this finding, carriers of the AGCC haplotype had higher circulating IL-10 levels in vivo. The common TLR4 polymorphisms (Asp299Gly and Thr399Ile) were associated with slightly higher IL-10 production capacity ex vivo and in vivo, however, this was not statistically significant. Our results indicate that polymorphisms in the proximal IL-10 promoter region are associated with in vivo and ex vivo LPS sensitivity. The contribution to the inter-individual variation, however, is limited since the variation between individuals in LPS sensitivity and IL-10 production capacity can only partly be attributed to these IL-10 promoter polymorphisms.
Cytokine 2005 Mar 07
PMID:IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin. 1576 Jun 78

Infiltration of polymorphonuclear neutrophils (PMNs) is thought to play a role in ischemic brain damage. The present study investigated the effect of repertaxin, a new noncompetitive allosteric inhibitor for the receptors of the inflammatory chemokine CXC ligand 8 (CXCL8)/interleukin-8 (IL-8), on PMN infiltration and tissue injury in rats. Cerebral ischemia was induced by permanent or transient occlusion of the middle cerebral artery and myeloperoxidase activity, a marker of PMN infiltration, and infarct volume were evaluated 24 h later. Repertaxin (15 mg/kg) was administered systemically at the time of ischemia and every 2 h for four times. In permanent ischemia repertaxin reduced PMN infiltration by 40% in the brain cortex but did not limit tissue damage. In transient ischemia (90-min ischemia followed by reperfusion), repertaxin inhibited PMN infiltration by 54% and gave 44% protection from tissue damage. Repertaxin had anti-inflammatory and neuroprotective effects also when given at reperfusion and even at 2 h of reperfusion. The protective effect of repertaxin did not interfere with brain levels of the chemokine. Since the PMN infiltration and its inhibition by repertaxin were comparable in the two models we conclude that reperfusion induces PMN activation, and inhibition of CXCL8 by repertaxin might be of pharmacological interest in transient ischemia.
Cytokine 2005 May 07
PMID:Neuroprotection with the CXCL8 inhibitor repertaxin in transient brain ischemia. 1582 19

We have previously demonstrated that intratracheal instillation (IT) with diesel exhaust particles (DEP) exacerbates myocardial ischemia/reperfusion-induced arrhythmia in rats. Since activated neutrophils play a pivotal role in ischemia/reperfusion arrhythmia, in the present study we investigated the effects of DEP on peripheral neutrophil count and on the oxyradical production (ORP) of neutrophils in rats. We also determined the production of cytokines for better understanding of the relationship between pulmonary inflammation and neutrophil function. Instillation with 5 mg DEP elevated circulatory neutrophil counts (CNC) at 12 and 24 h post-instillation to levels approximately 2.1- and 2.3-fold those in the vehicle-treated animals, respectively. On the other hand, 1-mg DEP caused an approximately 0.4-fold increase in CNC at 6 h. 12-O-Tetradecanoylphorbol 13-acetate-induced ORP in the isolated neutrophil was enhanced at 12 and 24 h after instillation with 5 mg DEP. Cytokine-induced neutrophil chemoattractant-1 (CINC-1), tumor necrosis factor-alpha (TNFalpha) and macrophage inflammatory protein-2 (MIP-2) levels were increased in the bronchoalveolar lavage fluid (BALF) collected from animals that received 5 mg DEP. In serum, a marked elevation of CINC-1 and a slight elevation of MIP-2 were also observed, while TNFalpha was not detected. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was detected in neither BALF nor serum for 24 h after the instillation. These results suggest that IT instillation of DEP enhances systemic oxidative stress by increasing neutrophil count and ORP in the acute period.
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PMID:Acute functional enhancement of circulatory neutrophils after intratracheal instillation with diesel exhaust particles in rats. 1608 73

Pretreatment with tumor necrosis factor-alpha (TNF-alpha) is known to trigger cardioprotection and it can activate multiple downstream signaling cascades. However, it is not known whether the mitochondrial permeability transition pore and the Ca(2+)-activated K(+) channel (K(Ca) channel) are involved in the TNF-alpha-induced cardioprotection. In the present study, we examined whether TNF-alpha inhibits pore opening and activates the K(Ca) channel in the cardioprotection. In isolated rat hearts subjected to 30 min of regional ischemia and 120 min of reperfusion, pretreatment with 10 U/ml TNF-alpha for 7 min followed by 10 min washout improved the recovery of rate-pressure product (RPP=left ventricular developed pressure x heart rate) and coronary flow (CF) during reperfusion, and reduced the infarct size and release of lactate dehydrogenase (LDH). Administration of 20 micromol/L atractyloside, a pore opener, for the last 5 min of ischemia and first 15 min of reperfusion, and pretreatment with 1 micromol/L paxilline, an inhibitor of the K(Ca) channel, for 5 min before ischemia, attenuated the recovery of RPP and CF, and the reductions of infarct size and release of LDH induced by TNF-alpha. On the other hand, administration of 10 micromol/L NS 1619, an opener of the K(Ca) channel, for 10 min before ischemia, decreased the infarct size and LDH release, and improved contractile functions and CF; these effects were attenuated by atractyloside. Pretreatment with 0.2 micromol/L cyclosporin A for the last 5 min of ischemia and first 15 min of reperfusion showed similar effects to those of TNF-alpha, and they were not attenuated by paxilline. In mitochondria isolated from hearts pretreated with 10 U/ml TNF-alpha for 7 min, a significant inhibition of Ca(2+)-induced swelling was observed. Furthermore, paxilline attenuated the inhibition of Ca(2+)-induced mitochondrial swelling by TNF-alpha. These findings indicate that TNF-alpha protects the myocardium against ischemia and reperfusion injury by inhibiting mitochondrial permeability transition pore opening as well as activating K(Ca) channels, probably the mitochondrial K(Ca) channel, which is upstream from the pore.
Cytokine 2005 Dec 07
PMID:The mitochondrial permeability transition pore and the Ca2+-activated K+ channel contribute to the cardioprotection conferred by tumor necrosis factor-alpha. 1626 Jan 45

Pro-inflammatory factors such as the adipokine leptin and cytokine tumor necrosis factor-alpha (TNFalpha) have been implicated in the onset of myocardial dysfunction in ischemia-reperfusion injury, sepsis, heart failure, viral myocarditis and cardiac allograft rejection. Although circulating TNFalpha and leptin levels are both elevated under a variety of inflammatory conditions, it remains unknown whether TNFalpha and leptin depress cardiac contractile function independently or synergistically. We examined the effect of acute (30 min) and short-term (24h) exposure of TNFalpha, leptin or both on cardiac contractile function in adult rat ventricular myocytes. Contractile properties were evaluated using an Ionoptix Softedge system including peak shortening (PS), maximal velocity of shortening/relengthening (+/-L/t), time-to-PS (TPS) and time-to-90% relengthening (TR(90)). Both TNFalpha (0.5-500 pg/ml) and leptin (1-100 nm) exerted concentration-dependent inhibitions in PS and +/-L/t following a 30-min exposure. TNFalpha but not leptin prolonged TR(90). Interestingly, TNFalpha-induced depression of cell shortening was masked by leptin and vice versa. Following a 24-h incubation, both TNFalpha and leptin significantly inhibited PS and +/-L/t without affecting TPS and TR(90). There was no additive or synergistic response by the two pro-inflammatory factors. The nitric oxide synthase inhibitor l-NMMA abolished depression of myocyte shortening elicited by TNFalpha, leptin or both. In summary, this study demonstrated that the inhibitory effect on cardiac contraction by TNFalpha and leptin may mask each other and share a common mechanism(s), probably dependent on NO.
Cytokine 2005 Dec 07
PMID:Interaction between tumor necrosis factor-alpha and leptin-induced inhibition of cardiac contractile function in isolated ventricular myocytes. 1629 37

HMGB1 was originally identified as a DNA-binding protein that functions as a structural co-factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be "passively released" into the extracellular milieu by necrotic and damaged somatic cells. Extracellular HMGB1 represents an optimal "necrotic marker" selected by the innate immune system to recognize tissue damage and initiate reparative responses. HMGB1 in the extracellular milieu promotes maturation of myeloid and plasmacytoid dendritic cells, and induces myocardial regeneration after infarction. However, extracellular HMGB1 also acts as a potent pro-inflammatory cytokine that contributes to the pathogenesis of diverse inflammatory and infectious disorders. A growing number of studies indicate that HMGB1 is a successful therapeutic target in experimental models of ischemia/reperfusion, acute respiratory distress syndrome, rheumatoid arthritis, sepsis, and cancer. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses while preventing its pathological potential. This article focus on the immuno-regulatory role of HMGB1 and its contribution to infectious and inflammatory disorders.
Cytokine Growth Factor Rev 2006 Jun
PMID:High-mobility group box 1 (HMGB1) protein: friend and foe. 1651 9

Numerous animal studies simulating liver injury have demonstrated that interleukin-6 (IL-6) exerts a protective effect. This study was designed to further analyze the molecular mechanisms underlying the protective role of IL-6 in a rat model of liver ischemia/reperfusion injury. We show that IL-6: (i) at high doses reduces cell damage which occurs in ischemic-reperfused liver, while at low doses displays only a limited protective capacity, (ii) anticipates and enhances hepatocyte compensatory proliferation seen in ischemic-reperfused liver also at a low, more pharmacologically acceptable dose, (iii) sustains the acute phase response which is dampened in ischemic-reperfused liver, (iv) strengthens the heat shock-stress response shown by ischemic-reperfused liver and (v) overcomes the dysfunctions of the unfolding protein response found in ischemic-reperfused liver. We also show that IL-6-enhanced STAT3 activation probably plays a crucial role in the potentiation of the different protective pathways activated in ischemic-reperfused liver. Our data confirm that IL-6 is a potential therapeutic in liver injury of different etiologies and reveal novel mechanisms by which IL-6 sustains liver function after ischemia/reperfusion injury.
Cytokine 2006 May
PMID:Mechanisms of interleukin-6 protection against ischemia-reperfusion injury in rat liver. 1681 59


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