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)

We recently found that 5-lipoxygenase (5-LOX) is activated to produce cysteinyl leukotrienes (CysLTs), and CysLTs may cause neuronal injury and astrocytosis through activation of CysLT(1) and CysLT(2) receptors in the brain after focal cerebral ischemia. However, the property of astrocyte responses to in vitro ischemic injury is not clear; whether 5-LOX, CysLTs, and their receptors are also involved in the responses of ischemic astrocytes remains unknown. In the present study, we performed oxygen-glucose deprivation (OGD) followed by recovery to induce ischemic-like injury in the cultured rat astrocytes. We found that 1-h OGD did not injure astrocytes (sub-lethal OGD) but induced astrocyte proliferation 48 and 72 h after recovery; whereas 4-h OGD moderately injured the cells (moderate OGD) and led to death 24-72 h after recovery. Inhibition of phospholipase A(2) and 5-LOX attenuated both the proliferation and death. Sub-lethal and moderate OGD enhanced the production of CysLTs that was inhibited by 5-LOX inhibitors. Sub-lethal OGD increased the expressions of CysLT(1) receptor mRNA and protein, while moderate OGD induced the expression of CysLT(2) receptor mRNA. Exogenously applied leukotriene D(4) (LTD(4)) induced astrocyte proliferation at 1-10 nM and astrocyte death at 100-1,000 nM. The CysLT(1) receptor antagonist montelukast attenuated astrocyte proliferation, the CysLT(2) receptor antagonist BAY cysLT2 reversed astrocyte death, and the dual CysLT receptor antagonist BAY u9773 exhibited both effects. In addition, LTD(4) (100 nM) increased the expression of CysLT(2) receptor mRNA. Thus, in vitro ischemia activates astrocyte 5-LOX to produce CysLTs, and CysLTs result in CysLT(1) receptor-mediated proliferation and CysLT(2) receptor-mediated death.
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PMID:Activation of CysLT receptors induces astrocyte proliferation and death after oxygen-glucose deprivation. 1791 51

The appropriate development of an inflammatory response is central for the ability of a host to deal with any infectious insult. However, excessive, misplaced, or uncontrolled inflammation may lead to acute or chronic diseases. The microbiota plays an important role in the control of inflammatory responsiveness. In this study, we investigated the role of lipoxin A4 and annexin-1 for the IL-10-dependent inflammatory hyporesponsiveness observed in germfree mice. Administration of a 15-epi-lipoxin A4 analog or an annexin-1-derived peptide to conventional mice prevented tissue injury, TNF-alpha production, and lethality after intestinal ischemia/reperfusion. This was associated with enhanced IL-10 production. Lipoxin A4 and annexin-1 failed to prevent reperfusion injury in IL-10-deficient mice. In germfree mice, there was enhanced expression of both lipoxin A4 and annexin-1. Blockade of lipoxin A4 synthesis with a 5-lipoxygenase inhibitor or Abs against annexin-1 partially prevented IL-10 production and this was accompanied by partial reversion of inflammatory hyporesponsiveness in germfree mice. Administration of BOC-1, an antagonist of ALX receptors (at which both lipoxin A4 and annexin-1 act), or simultaneous administration of 5-lipoxygenase inhibitor and anti-annexin-1 Abs, was associated with tissue injury, TNF-alpha production, and lethality similar to that found in conventional mice. Thus, our data demonstrate that inflammatory responsiveness is tightly controlled by the presence of the microbiota and that the innate capacity of germfree mice to produce IL-10 is secondary to their endogenous greater ability to produce lipoxin A4 and annexin-1.
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PMID:The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. 1805 1

The anti-inflammatory effects of pranlukast, an antagonist of cysteinyl leukotriene receptor 1, may be rendered not only by antileukotriene activity but also by other pharmacological activities. Previous studies indicate that pranlukast reduces ischemic tissue injury partially through decreasing vascular permeability, but its effect on ischemic injury in endothelial cells is not known. Thus, in this study, we investigated the effect of pranlukast on ischemia-like injury induced by oxygen-glucose deprivation (OGD) in EA.hy926 cells, a human endothelial cell line, and the possible mechanisms. We found that cell viability was reduced, lactate dehydrogenase release was increased 4-8 hours after OGD, and necrosis was induced 8 hours after OGD. Production of reactive oxygen species (ROS) increased by 211%, 176%, and 128%, respectively, 0.5, 1, and 2 hours after OGD. Nuclear factor-kappaB (NF-kappaB) was translocated to the nuclei 4-8 hours after OGD. Pranlukast ameliorated the reduced viability, the increased lactate dehydrogenase release, and necrosis after OGD. It also reduced ROS production and inhibited NF-kappaB nuclear translocation after OGD. The ROS scavenger, edaravone, inhibited OGD-induced nuclear translocation of NF-kappaB as well. Edaravone and pyrrolidine dithiocarbamate (a specific NF-kappaB inhibitor) protected endothelial cells from the OGD-induced injury. However, zileuton, a 5-lipoxygenase inhibitor, did not affect the cell injury, ROS production, and NF-kappaB nuclear translocation after OGD. The exogenous leukotriene D4 did not induce cell injury, ROS production, and NF-kappaB translocation. Thus, we conclude that pranlukast protects endothelial cells from ischemia-like injury via decreasing ROS production and inhibiting NF-kappaB activation, which is leukotriene independent.
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PMID:Pranlukast attenuates ischemia-like injury in endothelial cells via inhibiting reactive oxygen species production and nuclear factor-kappaB activation. 1912 32

The 5-lipoxygenase (5-LO) pathway is responsible for the production of leukotrienes (LTs), inflammatory lipid mediators which play a role in innate immunity. More recently, a pivotal role of LTs in ischemia-reperfusion and shock injury has been suggested. In fact, these pathological conditions are characterized by a severe neutrophil infiltration that gives rise to tissue injury and 5-LO metabolites control neutrophil recruitment in injured tissue by the modulation of adhesion molecule expression. The aim of this review is to analyze the results reported in the literature on the role of 5-LO pathway, with particular regard to LTs, in these pathological conditions. A better understanding of the mechanisms underlying the role of the 5-LO enzyme and/or its metabolites in the regulation of neutrophil trafficking, might open new perspectives in the therapy of organ dysfunction and/or injury associated with shock and ischemia-reperfusion injury.
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PMID:Involvement of leukotriene pathway in the pathogenesis of ischemia-reperfusion injury and septic and non-septic shock. 1935 2

The cerebral ischemia-reperfusion injury remains a major medical problem due to the lack of effective treatment. The mechanism of brain injury is still unknown. The defensive and offensive factors, such as platelet-derived growth factor-BB (PDGF-BB), 5-lipoxygenase (5-LO), aquaporin-4 (AQP-4) and insulin-like growth factor-1 (IGF-1) may play important roles. So far, only individual factors were reported. What are the relationships among them in brain ischemia-reperfusion injury remains obscure. The present study is to investigate simultaneously the expression of PDGF-BB, 5-LO, AQP-4 and IGF-1 in middle cerebral artery occlusion/reperfusion (MCAO/R) in rats. We found that 5-LO and IGF-1 reached the peak level at 24h after reperfusion, AQP-4 at 72 h and PDGF-BB at 7 days. With these results we inferred that both defensive factors, such as PDGF-BB, AQP-4 and IGF-1, and offensive factor, like 5-LO, play some roles in the ischemia-reperfusion injury.
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PMID:Longitudinal changes of defensive and offensive factors in focal cerebral ischemia-reperfusion in rats. 1944 8

Zileuton has been demonstrated to act as an anti-inflammatory agent by virtue of its well-known ability to inhibit 5-lipoxygenase (5-LO). However, the effects of zileuton on cardiovascular disease and cardiomyocyte apoptosis are unclear. Here, we investigated the effects of zileuton on apoptosis of cardiac myogenic H9c2 cells and neonatal rat cardiomyocytes (NRCMs), and examined the possible role of PKC delta-mediated induction of COX-2 in these effects. Treatment of H9c2 cells with zileuton efficiently induced COX-2 expression and PGE(2) biosynthesis in a time- and dose-dependent manner. Zileuton also exerted a profound protective effect against H(2)O(2)-induced oxidative stress, a mimic of reperfusion damage in vitro, and this protective effect was abolished by COX-2-selective inhibitor. When we investigated the signalling pathways involved in zileuton-induced COX-2 expression, we found that zileuton acts as a PKC delta activator, causing it to translocate from the cytosol to nucleus. Inhibition of PKC delta activation with rottlerlin, a PKC delta-specific inhibitor, abolished the zileuton-induced protection against H(2)O(2)-induced cell death and inhibited zileuton-induced COX-2 expression and PGE(2) production. The protective effect of zileuton was dramatically diminished by treatment with LY294002 or PD98059. Furthermore, zileuton-stimulated ERK1/2 and Akt phosphorylation was attenuated by rottlerin, indicating that PKC delta might act upstream of ERK1/2 and Akt. Moreover, inhibition of either ERK1/2 or Akt activation abolished zileuton-induced COX-2 expression. Knockdown of PKC delta with siRNA also reversed the protective effect of zileuton and blocked the induction of COX-2. These results suggest that zileuton-induced COX-2 expression is sequentially mediated through PKC delta-dependent activation of ERK1/2 and Akt. Based on these findings, we propose that zileuton might provide a new therapeutic strategy for ischemia/reperfusion injury of the heart.
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PMID:The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta. 1978 29

Rat gastric mucosal damage was induced by ischemia-reperfusion. The 5-lipoxygenase inhibitors MK886 and A63162, the 12-lipoxygenase inhibitor baicalein, the 15-lipoxygenase inhibitor PD146176 and the lipoxin (LX) A(4)/annexin 1 antagonist Boc1 increased mucosal damage in a dose-dependent manner. Low doses of these compounds, which have no effects on mucosal integrity, cause severe damage when combined with low doses of indomethacin, celecoxib or dexamethasone. 16,16-Dimethylprostaglandin (PG) E(2) and LXA(4) can replace each other in preventing mucosal injury induced by either cyclooxygenase or lipoxygenase inhibitors. The results suggest that not only cyclooxygenases, but also lipoxygenases have a role in limiting gastric mucosal damage during ischemia-reperfusion.
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PMID:Role of lipoxygenases and the lipoxin A(4)/annexin 1 receptor in ischemia-reperfusion-induced gastric mucosal damage in rats. 1981 89

The role of cyclooxygenases and prostaglandins in experimental models of gastroprotection is well established. We investigated the effects of the 5-lipoxygenase inhibitor A63162, the 12-lipoxygenase inhibitor baicalein and the 15-lipoxygenase inhibitor PD146176 as well as the nonspecific lipoxin A(4)/annexin-1 antagonist Boc1 on adaptive protection induced by 20% ethanol against 70% ethanol, and on protection induced by sodium salicylate against the mucosal-damage-aggravating effects of celecoxib and dexamethasone during local ischemia-reperfusion in rats. It was found that both types of gastroprotection were antagonized by the lipoxygenase inhibitors and the lipoxin A(4)/annexin-1 antagonist in doses that have no direct damaging effect on gastric mucosa. The results suggest that not only cyclooxygenases, but also active lipoxygenases and, possibly, annexin-1 are required for these types of gastroprotection to occur.
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PMID:Role of lipoxygenases and lipoxin A(4)/annexin-1 receptor in gastric protection induced by 20% ethanol or sodium salicylate in rats. 1984 31

It is well known that 5-lipoxygenase derivates of arachidonic acid play an important pathogenic role during myocardial infarction. Therefore, the gene encoding arachidonate 5-lipoxygenase (ALOX5) appears to be an attractive target for RNA interference (RNAi) application. In experiments on cultivated cardiomyocytes with anoxia-reoxygenation (AR) and in vivo using rat model of heart ischemia-reperfusion (IR) we determined influence of ALOX5 silencing on myocardial cell death. ALOX5 silencing was quantified using real-time PCR, semi-quantitative PCR, and evaluation of LTC(4) concentration in cardiac tissue. A 4.7-fold decrease of ALOX5 expression (P < 0.05) was observed in isolated cardiomyocytes together with a reduced number of necrotic cardiomyocytes (P < 0.05), increased number live (P < 0.05) and unchanged number of apoptotic cells during AR of cardiomyocytes. Downregulation of ALOX5 expression in myocardial tissue by 19% (P < 0.05) resulted in a 3.8-fold reduction of infarct size in an open chest rat model of heart IR (P < 0.05). Thus, RNAi targeting of ALOX5 protects heart cells against IR injury both in culture and in vivo.
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PMID:Cardioprotective effect of 5-lipoxygenase gene (ALOX5) silencing in ischemia-reperfusion. 2001 86

We examined the role of cysteinyl leukotrienes (CysLTs) in the gastric ulcerogenic response to ischemia/reperfusion (I/R) in mice. Experiments were performed in male C57BL/6J mice after 18-h fasting. Under urethane anesthesia, the celiac artery was clamped for 30 min, and then reperfusion was achieved by removing the clamp. The stomach was examined for lesions 60 min thereafter. The severity of I/R-induced gastric damage was reduced by prior administration of pranlukast [CysLT receptor type 1 (CysLT(1)R) antagonist] as well as 1-[[5'-(3''-methoxy-4''-ethoxycarbonyl-oxyphenyl)-2',4'-pentadienoyl]aminoethyl]-4-diphenylmethoxypiperidine [TMK688; 5-lipoxygenase (5-LOX) inhibitor]. On the contrary, these lesions were markedly worsened by pretreatment with indomethacin, and this response was abrogated by the coadministration of TMK688 or pranlukast. The gene expression of CysLT(1)R but not 5-LOX was up-regulated in the stomach after I/R, but both expressions were increased under I/R in the presence of indomethacin. I/R slightly increased the mucosal CysLT content of the stomach, yet this increase was markedly enhanced when the animals were pretreated with indomethacin. The increased CysLT biosynthetic response to indomethacin during I/R was attenuated by TMK688. Indomethacin alone caused a slight increase of CysLT(1)R expression and markedly up-regulated 5-LOX expression in the stomach. We concluded that I/R up-regulated the expression of CysLT(1)R in the stomach; CysLTs play a role in the pathogenesis of I/R-induced gastric damage through the activation of CysLT(1)R; and the aggravation by indomethacin of these lesions may be brought about by the increase of CysLT production and the up-regulation of 5-LOX expression, in addition to the decreased prostaglandin production.
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PMID:Pathogenic importance of cysteinyl leukotrienes in development of gastric lesions induced by ischemia/reperfusion in mice. 2004 30


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