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)

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.
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PMID:Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. 1062 51

Little is known about interactions between endogenous anti-inflammatory paradigms and microvascular thrombosis in lung ischemia/reperfusion (I/R) injury. Interleukin (IL)-10 suppresses macrophage activation and down-regulates proinflammatory cytokine production, but there are no available data to suggest a link between IL-10, thrombosis, and fibrinolysis in the setting of I/R. We hypothesized that hypoxia/ischemia triggers IL-10 production, to dampen proinflammatory cytokine and adhesion receptor cascades and to restore vascular patency by fibrinolytic potentiation. Studies were performed in a mouse lung I/R model. IL-10 mRNA levels in lung were increased 43-fold over base line by 1 h of ischemia/2 h of reperfusion, with a corresponding increase in plasma IL-10. Expression was prominently localized in bronchial epithelial cells and mononuclear phagocytes. To study the link between IL-10 and fibrinolysis in vivo, the induction of plasminogen activator inhibitor-1 (PAI-1) was evaluated. Northern analysis demonstrated exaggerated pulmonary PAI-1 expression in IL-10 (-/-) mice after I/R, with a corresponding increase in plasma PAI/tissue-type plasminogen activator activity. In vivo, IL-10 (-/-) mice showed poor postischemic lung function and survival after I/R compared with IL-10 (+/+) mice. Despite a decrease in infiltration of mononuclear phagocytes in I/R lungs of IL-10 (-/-) mice, an increased intravascular pulmonary fibrin deposition was observed by immunohistochemistry and Western blotting, along with increased IL-1 expression. Recombinant IL-10 given to IL-10 (-/-) mice normalized the PAI/tissue-type plasminogen activator ratio, reduced pulmonary vascular fibrin deposition, and rescued mice from lung injury. Since recombinant hirudin (direct thrombin inhibitor) also sufficed to rescue IL-10 (-/-) mice, these data suggest a preeminent role for microvascular thrombosis in I/R lung injury. Ischemia-driven IL-10 expression confers postischemic pulmonary protection by augmenting endogenous fibrinolytic mechanisms.
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PMID:Potentiation of endogenous fibrinolysis and rescue from lung ischemia/reperfusion injury in interleukin (IL)-10-reconstituted IL-10 null mice. 1080 8

The results of recent anticytokine trials for sepsis syndrome have been disappointing. Several Phase II and Phase III clinical trials have shown a modest benefit in various subsets of patients; however, there has been no reported benefit in the primary endpoint of 28-day all-cause mortality. The failure of these trials is clearly multifactorial, and causes include the overall complexity of the inflammatory response, heterogeneity of the patient populations, absence of a hypercytokine response at the time of drug treatment, and the relatively short half-life of the administered drugs. The failure of anticytokine therapies may represent inadequate application of the treatment modality rather than any inherent weakness of the treatment itself. We have recently initiated a Phase I clinical trial examining the role of the anti-inflammatory cytokine IL-10 during surgical repair of a thoracoabdominal aortic aneurysm. This study may overcome some of the-design limitations of previous anticytokine trials in sepsis, and serve as a paradigm for future anticytokine therapy trials. Although the incidence of thoracoabdominal aortic aneurysms is relatively low, the patient population is homogeneous and the surgical injury associated with its repair reproducible. Additionally, postoperative mortality and morbidity rates are significant. Most importantly, the operative repair is associated with an obligatory visceral ischemia and reperfusion injury that appears to be associated with a proinflammatory cytokine response and postoperative organ dysfunction. IL-10 is a pleuripotent anti-inflammatory cytokine that both inhibits TNFalpha and IL-1 synthesis, and antagonizes their actions through upregulation of cytokine antagonists. Furthermore, IL-10 administration has been associated with only minimal adverse side effects during Phase I and Phase II trials.
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PMID:Anticytokine therapies for acute inflammation and the systemic inflammatory response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm. 1084 28

Heme oxygenase-1, an inducible heat shock protein, is upregulated by oxidative stress, and its expression is modulated by proinflammatory cytokines such as IL-1 and IL-6. In the present study, we investigated the effects of postlesional, orally applied ebselen, a neuroprotective antioxidant, on serum levels of IL-6 and cerebral heme oxygenase-1 expression following focal ischemia induced by photothrombosis. Ebselen (50 mg/kg body weight) was given 30 min postlesion to male Wistar rats. Animals were divided into four groups: sham-operated vehicle control (n = 9), sham-operated ebselen control (n = 8), lesioned vehicle control (n = 14), and lesioned ebselen-treated (n = 17). Ebselen treatment resulted in a significant lowering of IL-6 plasma levels (26 +/- 5 pg/ml) as compared with that seen in lesioned vehicle controls (48 +/- 9 pg/ml) at 24 h postlesion. In sham-operated rats IL-6 was not detectable. Heme oxygenase-1-positive glial cells were quantitated within topographically determined perilesional brain regions. Within the 0.5-mm-wide rim region directly associated with the lesion core, no differences in the amount of heme oxygenase-1-positive glial cells were found. However, in the more remote ipsilateral perilesional cortex, significantly fewer heme oxygenase-1-positive glial cells were present within the supragranular cortical layers of lesioned ebselen-treated rats compared to lesioned vehicle controls (P < 0.001). In sham-operated rats, no glial heme oxygenase-1 induction occurred. The results indicate that postlesional ebselen treatment lowered plasma IL-6 levels subsequent to a photothrombotic lesion concomitant with a lowering of the heme oxygenase-1 response in glial cells.
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PMID:Ebselen lowers plasma interleukin-6 levels and glial heme oxygenase-1 expression after focal photothrombotic brain ischemia. 1093 77

The systemic inflammatory response (SIRS) results from various types of injuries such as severe infection, trauma, ischemia-reperfusion and major surgery including cardiac surgery with cardio-pulmonary bypass. This response involves immune cell activation and a complex network of proinflammatory cytokines, which may induce multiple organ failure when uncontrolled. The monocyte plays a central role in the response to infection with the release of TNF, IL-1, and IL-12. In addition, monocytes present antigens to T lymphocytes. An optimal antigen presentation requires the expression of MHC class II HLA-DR on monocytes surface and of co-stimulatory molecules such as CD54 on monocytes and LFA-1 on lymphocytes. It has become increasingly apparent that the pro-inflammatory response is balanced by concomitant anti-inflammatory mechanisms that results in monocyte deactivation, characterized by a decrease in HLA-DR expression and the release of anti-inflammatory cytokines such as IL-10. This counterregulatory response, if prolonged or predominant, may predispose the patient to a higher risk of infection. Further studies need to be conducted to precise: 1) the intensity of depression of the surface molecule expression assessing monocyte function, such as HLA DR and CD54; 2) the level of IL-10 and IL-12 release in patients with severe sepsis; 3) the immunomodulating effects of frequently used treatments in these patients with severe sepsis and in surgical patients; 4) the time course of recovery; 5) if the monitoring of HLA-DR, CD54, IL-10 and IL-12 will better predict the clinical outcome than clinical parameters.
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PMID:Assessment of immunological status in the critically ill. 1096 15

This study was designed to evaluate the possible role of cytokines (IL-1 and TNF-alpha) in the pathogenesis of pancreatic injuries induced by pancreatic ischemia-reperfusion and to evaluate the protective effect of the cytokine suppressive agent, FR167653, against pancreatic injuries. Pancreatic ischemia-reperfusion was induced in rats by ligating the celiac and caudate mesenteric arteries by small metallic clips for 45 min, after this ischemia, the metal clips were removed. Four hours after removing the metal clips, the animals were used for the experiments. In this model, mild hyperamylsemia and significant increases in pancreatic water and trypsin content were observed. Significant increases in serum IL-1 and TNF-alpha were also observed, as compared with the control rats. Pancreatic subcellular redistribution of lysosomal enzyme cathepsin B from the lysosomal fraction to the zymogen fraction was also observed. However, treatment with FR167653 at a dose of 0.5 mg/kg.hr significantly prevented all these pancreatic injuries. These results indicate that cytokines such as IL-1 and TNF-alpha might be involved in the pathogenesis of pancreatic injuries induced by ischemia-reperfusion, and that a cytokine suppressive agent might be of therapeutic value for the treatment of pancreatic ischemia.
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PMID:Cytokine Suppressive Agent Prevents Pancreatic Injuries Induced by Ischemia-Reperfusion in Rats. 1106 14

The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I/R resulted in improved contractile function after I/R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I/R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg/mg vs. I/R, 26 pg/mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1beta-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I/R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1beta, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1beta play a significant role in I/R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1beta and thereby prevents ischemia-induced myocardial dysfunction.
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PMID:Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. 1122 33

Ischaemia/reperfusion (I/R) lung injury using University of Wisconsin solution (UW) as perfusate has not been well studied. Isolated rat lungs were challenged with various periods of ischaemia and/or reperfusion. Haemodynamics, lung weight gain (LWG), capillary filtration coefficient (K(fc)), tissue pathology, the concentrations of cytokines in the perfusate, and mRNAs for the various cytokines in the lung tissues were measured. I/R induced a permeability type of pulmonary oedema, as reflected by increases in LWG and K(fc). LWG and K(fc) in the I(45)R(60)(UW) group (45 min of ischaemia followed by 60 min of reperfusion with UW) were only 2% and 5% respectively of those in the I(45)R(60)(NS) group (where NS is normal saline). LWG and K(fc) in the UW group had both increased by 180 min, to values similar to those in the I(45)R(60)(NS) group. However, these findings show that UW was remarkably effective at preventing LWG after 60 min of reperfusion, and was more than 3-fold more effective than NS in delaying LWG. For longer ischaemic times only, or the same period of ischaemia followed by longer reperfusion periods, greater lung injury occurred. I/R lung injury also induced increased concentrations of tumour necrosis factor-alpha (TNF-alpha), interleukin 1 and interleukin 6 in the perfusate, and increased the mRNAs for these cytokines in lung tissue. A significant correlation was obtained between TNF-alpha concentration and LWG. TNF-alpha production in the I(45)R(60)(UW) group was only 7% of that in the I(45)R(60)(NS) group. However, TNF-alpha mRNA expression in the I(45)R(60)(UW) group was 80% of that in the I(45)R(60)(NS) group. This indicates that transcription/translation do not correlate well with cytokine production, and also suggests that one reason for the effectiveness of UW in delaying LWG may be because it delays TNF-alpha production. In summary, ischaemia or I/R caused a permeability-type pulmonary oedema that was associated with leucocyte infiltration and the up-regulation of various cytokines, regardless of the perfusion fluid. Except for pulmonary hypertension, less severe I/R lung injury and delayed cytokine production in lungs perfused with UW, the pattern of injury associated with I/R challenge was similar to that in lungs perfused with NS. We propose that more or long-acting protective agents are required as additives in order to modify UW to produce an optimal preservation solution.
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PMID:Cytokine up-regulation in ischaemic/reperfused lungs perfused with University of Wisconsin solution and normal saline. 1152 46

The cytokine interleukin-1beta (IL-1beta) contributes to ischemic, excitotoxic, and traumatic brain injury. IL-1beta actions depend on interaction with a single receptor (IL-1RI), which associates with an accessory protein (IL-1RAcP), and is blocked by IL-1 receptor antagonist (IL-1ra). Here we show that in normal mice [wild-type (WT)], intracerebroventricular injection of IL-1ra markedly reduces (-50%; p < 0.01) ischemic brain damage caused by reversible occlusion of the middle cerebral artery, whereas injection of IL-1beta exacerbates damage (+45%; p < 0.05). Mice lacking IL-1RI [IL-1RI knock-out (KO)] exhibited ischemic brain damage that is almost identical to that of the WT (infarct volume 43.7 +/- 6.1 and 46.2 +/- 6.2 mm3, respectively), but failed to respond to injection of IL-1ra. However, injection of IL-1beta (intracerebroventricularly) exacerbated ischemic brain damage in IL-1RI KO (+61%; p < 0.001) and in WT mice (+45%). This effect of IL-1beta was abolished by heat denaturation in all animals, and was reversed by IL-1ra in WT, but not IL-1RI KO mice. In contrast, IL-1RI KO mice were completely resistant to effects of IL-1beta on food intake or body weight. IL-1RAcP mRNA was increased by stroke in WT, but reduced in IL-1RI KO mice compared with sham-operated mice. Type II IL-1 receptor mRNA was significantly increased 4 hr after ischemia in WT and IL-1RI KO (+20%) animals. These data show that IL-1beta can exacerbate ischemic brain damage independently of IL-1RI and suggest the existence of additional signaling receptor or receptors for IL-1 in the brain.
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PMID:Interleukin-1 influences ischemic brain damage in the mouse independently of the interleukin-1 type I receptor. 1175 86

The present study investigated the activation of extracellular-signal-regulated kinase (ERK) and the potential role of interleukin-1 beta (IL-1beta) in the brain's response to focal brain ischemia in the permanent middle cerebral artery occlusion (pMCAO) model. Phosphorylated ERK p44 and p42 were increased time-dependently and significantly 18- and 28-fold, respectively, at 24-h post-pMCAO. Similarly, IL-1beta protein levels were significantly increased with the peak at 24 h in the lesioned core of the ischemic hemisphere compared to the contralateral side. Previous studies using various stimuli have shown ERK-dependent IL-1 induction. The results from our study suggest that this relation may also exist in vivo in ischemic brain tissue. Based on the progressive nature of IL-1 induction, we hypothetized that inhibition of interleukin-converting enzyme (ICE) could provide an extended time-window for neuroprotection. Therefore, we applied N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD x fmk), an ICE blocker 3 or 6 h after pMCAO. Reductions of infarct volume, however, were not observed. Taken together with previous results, where we showed protective activity of zVAD x fmk when given immediately after pMCAO, we conclude that the time window for zVAD x fmk is less than 3 h.
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PMID:Similar time-course of interleukin-1 beta production and extracellular-signal-regulated kinase (ERK) activation in permanent focal brain ischemic injury. 1232 83


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