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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The production of cytokines directly from cardiac myocytes has not been previously demonstrated and could represent an important mechanism and site of intervention in ischemia and reperfusion injuries. Macrophage inflammatory protein-2 (MIP-2) and monocyte chemotactic protein (MCP) are chemotactic cytokines (chemokines) that stimulate polymorphonuclear leukocytes (PMNs) and monocytes, respectively. Endothelium has been implicated as being a major cellular source of leukocyte-activating factors. We hypothesized that the myocardial cells may also play an important role in producing chemokines independently of endothelium. Primary cultures of adult rat ventricular myocytes were prepared. Cultured myocytes were stimulated with either interleukin 1 (IL-1), tumor necrosis factor (TNF), or lipopolysaccharide (LPS). MIP-2 and MCP mRNA were expressed in adult rat myocytes following stimulation. Our studies indicate that ventricular myocytes expressed chemokine mRNA and protein in both a dose- and time-dependent fashion. MIP-2 and MCP release, determined by enzyme-linked immunosorbent assay, was biologically active, accounting for approximately 40% of the PMN and monocyte chemotactic activity produced by these cells. These results suggest that cardiac myocytes may directly recruit activated leukocytes into areas of injury. Such a recruiting process could underlie the migration of leukocytes into areas of oxidant stress and play a role in development of reperfusion injury of myocardium.
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PMID:Cardiac myocytes release leukocyte-stimulating factors. 757 43

Chemokine expression is associated with reperfusion of infarcted myocardium in the setting of tissue necrosis, intense inflammation, and inflammatory cytokine release. The specific synthesis of monocyte chemotactic protein (MCP)-1 mRNA by cardiac venules in reperfused infarcts corresponded to the region where leukocytes normally localize. MCP-1 could be induced by exogenous tumor necrosis factor (TNF)-alpha or by postischemic cardiac lymph containing TNF-alpha. However, the release of TNF-alpha during early reperfusion did not explain the venular localization of MCP-1 induction. To better understand the factors mediating MCP-1 induction, we examined the role of ischemia/reperfusion in a model of brief coronary occlusion in which no necrosis or inflammatory response is seen. Adult mongrel dogs were subjected to 15 minutes of coronary occlusion and 5 hours of reperfusion. Ribonuclease protection assay revealed up-regulation of MCP-1 mRNA only in ischemic segments of reperfused canine myocardium. Pretreatment with the reactive oxygen scavenger N-(2-mercaptopropionyl)-glycine completely inhibited MCP-1 induction. In situ hybridization localized MCP-1 message to small venular endothelium in ischemic areas without myocyte necrosis. Gel shift analysis of nuclear extracts from the ischemic area showed enhanced DNA binding of the transcription factors AP-1 and nuclear factor (NF)-kappaB, crucial for MCP-1 expression, in ischemic myocardial regions. Immunohistochemical staining demonstrated reperfusion-dependent nuclear translocation of c-Jun and NF-kappaB (p65) in small venular endothelium, only in the ischemic regions of the myocardium, that was inhibited by N-(2-mercaptopropionyl)-glycine. In vitro, treatment of cultured canine jugular vein endothelial cells with the reactive oxygen intermediate H2O2 induced a concentration-dependent increase in MCP-1 mRNA levels, which was inhibited by the antioxidant N-acetyl-L-cysteine, a precursor of glutathione, but not pyrrolidine dithiocarbamate, an inhibitor of NF-kappaB and activator of AP-1. In contrast to our studies with infarction, incubation of canine jugular vein endothelial cells with postischemic cardiac lymph did not induce MCP-1 mRNA expression suggesting the absence of cytokine-mediated MCP-1 induction after a sublethal ischemic period. These results suggest that reactive oxygen intermediate generation, after a brief ischemic episode, is capable of inducing MCP-1 expression in venular endothelium through AP-1 and NF-kappaB. Short periods of ischemia/reperfusion, insufficient to produce a myocardial infarction, induce MCP-1 expression, potentially mediating angiogenesis in the ischemic noninfarcted heart.
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PMID:Reactive oxygen intermediates induce monocyte chemotactic protein-1 in vascular endothelium after brief ischemia. 1158 58

Vascular endothelial growth factor (VEGF) is known to play an important role in angiogenesis. Its place in collateral artery growth (arteriogenesis), however, is still debated. In the present study, we analyzed the expression of VEGF and its receptors (Flk-1 and Flt-1) in a rabbit model of collateral artery growth after femoral artery occlusion. Hypoxia presents the most important stimulus for VEGF expression. We therefore also investigated the expression level of distinct hypoxia-inducible genes (HIF-1alpha, LDH A) and determined metabolic intermediates indicative for ischemia (ATP, creatine phosphate, and their catabolites). We found that arteriogenesis was not associated with an increased expression of VEGF or the mentioned hypoxia-inducible genes. Furthermore, the high-energy phosphates and their catabolites were entirely within normal limits. Despite the absence of an increased expression of VEGF and its receptors, collateral vessels increased their diameter by a factor of 10. The speed of collateral development could be increased by infusion of the chemoattractant monocyte chemotactic protein-1 but not by infusion of a 30 times higher concentration of VEGF. From these data, we conclude that under nonischemic conditions, arteriogenesis is neither associated with nor inducible by increased levels of VEGF and that VEGF is not a natural agent to induce arteriogenesis in vivo.
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PMID:Role of ischemia and of hypoxia-inducible genes in arteriogenesis after femoral artery occlusion in the rabbit. 1167 2

The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor whose activation regulates metabolism and inflammation. Recent data indicate that the zinc finger transcription factor early growth response gene-1 (Egr-1) acts as a master switch for the inflammatory response in ischemic vessels. Experiments tested the hypothesis that activation of endogenous PPAR-gamma inhibits induction of Egr-1. Egr-1 is rapidly induced in murine lungs after ischemia-reperfusion, as well as in alveolar mononuclear phagocytes deprived of oxygen as an ischemic model. In vitro, the natural PPAR-gamma ligand (15-deoxy-Delta12,14-prostaglandin J2) and a PPAR-gamma activator (troglitazone), but not a PPAR-alpha activator (bezafibrate), strikingly diminished Egr-1 mRNA and protein expression and nuclear DNA binding activity corresponding to Egr-1. In vivo, treatment with troglitazone before ischemia prevented induction of Egr-1 and its target genes such as interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-2. As a consequence of PPAR-gamma activation, pulmonary leukostasis was decreased and oxygenation and overall survival were improved. Activation of PPAR-gamma suppresses activation of Egr-1 and its inflammatory gene targets and provides potent protection against ischemic pulmonary injury. These data reveal a new mechanism whereby PPAR-gamma activation may decrease tissue inflammation in response to an ischemic insult.
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PMID:Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets. 1246 49

Macrophages are important participants in neovascularization. This study was designed to examine the role of the monocyte/macrophage chemotactic proteins, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1alpha (MIP-1alpha) in a mouse model of oxygen-induced ischemic retinopathy and to determine whether the morphology and distribution of macrophages/microglia are concomitantly altered. The MCP-1, MIP-1alpha mRNA levels increased at 3 h after ischemia. MCP-1, MIP-1alpha, and vascular endothelial growth factor protein levels were also increased markedly and were maximal on days 1, 0.5, and 1, respectively, after ischemia. In situ hybridization showed that MCP-1 and MIP-1alpha were localized in the hypoxic inner retina. Immunostaining demonstrated that the macrophages/microglia in the retina had morphological changes with enlarged processes, and some were closely associated with neovascular tufts at postnatal day 17. Coadministration of the neutralizing antibodies against MCP-1 and MIP-1alpha inhibited retinal neovascularization by 30%. Our data suggest that MCP-1 and MIP-1alpha are involved in the induction of retinal neovascularization and play a role in the inflammation induced by the ischemic retinopathy, possibly by modulating or attracting macrophages/microglia.
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PMID:Role of MCP-1 and MIP-1alpha in retinal neovascularization during postischemic inflammation in a mouse model of retinal neovascularization. 1252 71

Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e), a selective agonist of the A(2A) adenosine receptor (A(2A)AR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A(2A)AR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1alpha, IL-1beta, IL-1Ra, IL-6, IL-10, IL-18, INF-beta, INF-gamma, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1alpha, MIP-2, IFN-gamma-inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A(2A)AR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A(2A)AR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A(2A)AR agonist ATL146e.
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PMID:Protection from ischemic liver injury by activation of A2A adenosine receptors during reperfusion: inhibition of chemokine induction. 1471 20

Tumor necrosis factor-alpha (TNF-alpha) has two forms with apparently different biological activities: a membrane-associated form and a soluble form. TNF-alpha-converting enzyme (TACE) mediates a cleavage of membrane-associated TNF-alpha to induce its bioactive soluble form. We hypothesized that inhibition of TACE might prevent TNF-alpha-induced tissue injury while preserving the benefits of TNF-alpha. In this study, we evaluated the role of TACE in acute inflammation using an inhibitor of the enzyme in a rat model of lung transplantation. Inbred Lewis rats underwent left lung isotransplantation, and the donor lungs were kept in Euro-Collins solution with or without the inhibitor. After 6 hours of ischemia, the left lung was transplanted into the recipient rat and reperfused for 4 hours. Inhibition of TACE significantly attenuated endothelial and alveolar septal damage, as assessed by radiolabeled albumin leakage after transplantation. The inhibition also attenuated neutrophil accumulation in the alveolar space and other histopathologic findings, including intercellular adhesion molecule-1 expression. In addition, significantly lower levels of monocyte chemotactic protein-1, cytokine-induced neutrophil chemoattractant-1, high mobility group box-1, and soluble epithelial cadherin and decreased neutrophil elastase activity were observed in bronchoalveolar lavage fluid from the rats treated with the inhibitor. We conclude that TACE mediates a critical step in the development of post-transplantation lung injury.
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PMID:Importance of tumor necrosis factor-alpha cleavage process in post-transplantation lung injury in rats. 1533 31

Chronic ethanol-induced liver injury follows a typical progression from its earliest stage of steatosis to more advanced injury, characterized by the development of inflammation, hepatocyte necrosis/apoptosis, fibrosis and finally cirrhosis. Kupffer cells, the resident macrophage in the liver, play a critical role in the progression of liver injury. Increased exposure of Kupffer cells to lipopolysaccharide (LPS) during chronic ethanol exposure leads to the production of a number of inflammatory mediators, including tumor necrosis factor alpha (TNF-alpha). Recent evidence indicates that in addition to increased exposure to LPS, Kupffer cells also develop an enhanced sensitivity to LPS after chronic ethanol feeding. We have recently identified early growth response-1 (Egr-1), an immediate-early gene transcription factor, as an important contributor to increased LPS-stimulated TNF-alpha secretion by Kupffer cells after chronic ethanol exposure. In other models of tissue injury, such as ischemia-reperfusion in the lung, Egr-1 acts as a coordinator of the complex response to stress. Here we review the literature regarding the role of EGR-1 in regulation of a number of genes implicated in each of the stages of chronic ethanol-induced liver injury. In addition to the critical role of Egr-1 in generating maximal LPS-stimulated TNF-alpha expression, Egr-1 also controls the expression of a number of inflammatory mediators, including intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2, as well as genes contributing to fibrosis, such as transforming growth factor (TFG)-beta1, platelet-derived growth factor PDGF-A chain and fibroblast growth factor (FGF). Understanding the contribution of Egr-1 to the expression of genes involved in the development of chronic ethanol-induced liver injury may lead to the development of improved therapies designed to prevent and/or reverse alcohol-induced liver injury.
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PMID:Ethanol-induced liver injury: potential roles for egr-1. 1634

Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2-/- and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2-/- compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2-/- animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2-/- mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm(2) postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2-/- mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2-/- mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.
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PMID:Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury. 1702 Sep 36

Chemokines (chemotactic cytokines) are important in the recruitment of leukocytes to injured tissues and, as such, play a pivotal role in arteriogenesis and the tissue response to ischemia. Hind limb ischemia represents a complex model with arteriogenesis (collateral artery formation) occurring in tissues with normal perfusion while areas exhibiting ischemic necrosis undergo angiogenesis and skeletal muscle regeneration; monocytes and macrophages play an important role in all three of these processes. In addition to leukocyte trafficking, chemokines are produced by and chemokine receptors are present on diverse cell types, including myoblasts, endothelial, and smooth muscle cells. Thus, the chemokine system may have direct effects as well as inflammatory-mediated effects on arteriogenesis, angiogenesis, and skeletal muscle regeneration. This article reviews the complexity of the hind limb ischemia model and the role of the chemokine system in arteriogenesis and the tissue response to ischemia. Special emphasis will be placed on the roles of monocytes/macrophages and CCL2/monocyte chemotactic protein-1 (MCP-1) in these processes.
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PMID:The chemokine system in arteriogenesis and hind limb ischemia. 1754 24


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