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)

The proinflammatory chemokine interleukin-8 (IL-8/NAP-1) has been implicated in recruiting neutrophils to sites of acute and chronic tissue inflammation. In transgenic mice, elevated serum IL-8 levels ranging from 1 to 118 ng/ml were correlated with proportional increases in circulating neutrophils and proportional decreases in L-selectin expression on the surface of blood neutrophils. No change in the expression of the beta 2-integrins Mac-1 and LFA-1 was apparent on peripheral blood neutrophils of the IL-8 transgenic mice. Additionally, L-selectin expression on bone marrow neutrophils and neutrophil precursors was normal in all transgenic lines. IL-8 transgenic mice demonstrated an accumulation of neutrophils in the microcirculation of the lung, liver and spleen. Moreover, there was no evidence of neutrophil extravasation, plasma exudation or tissue damage in any IL-8 transgenic mice. Neutrophil migration into the inflamed peritoneal cavity was severely inhibited in IL-8 transgenic mice, but not in nontransgenic littermates. The IL-8 transgenic mice should serve as useful models for studying the putative role of neutrophils in mediating tissue damage in models of inflammation, such as hepatic ischemia and reperfusion injury, cecal puncture and ligation, and glomerulonephritis.
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PMID:Long-term impaired neutrophil migration in mice overexpressing human interleukin-8. 752 86

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

Interleukin 8 (IL-8) is one of the most widely studied chemoattractants for leukocytes. It belongs to the newly classified CXC family of chemokine which possesses biological activities mainly on neutrophils. The potential role of IL-8 in inflammation is substantiated by the growing evidences of clinical relevance of IL-8 in various diseases such as infection, ischemia and autoimmune disorders. The common characteristic pathological feature of these events is neutrophil infiltration. Although little is known about the mechanism of neutrophil recruitment into the urine, urinary tract infections (UTI) are accompanied by pyuria. Elevated urinary IL-8 levels were found in patients with UTI. Bioactive, multiple forms of IL-8 were produced locally within the urinary tract, and implied that IL-8 participated in the induction of neutrophil migration into the inflammatory site. Similar findings were observed in the peritoneal dialysate of patients on continuous ambulatory peritoneal dialysis with peritonitis. The notion of involvement of IL-8 in local infection was reinforced by the findings obtained on the rabbit UTI model. Finally, the clinical usefulness, as well as the problems of IL-8 level determination in various body fluids are discussed.
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PMID:[Interleukin-8]. 773 11

Cytokine-induced neutrophil chemoattractant (CINC), originally identified as a chemoattractant in rat kidney epithelial cells, is related to human 'gro' and murine 'KC'. The proteins encoded by these genes belong to the chemokine alpha superfamily, most of which have neutrophil chemotactic activity. Since brain chemokines may play a significant role in neutrophil accumulation in cerebral ischemia which can contribute to the extent of tissue injury in stroke, we examined the expression of CINC mRNA in the cerebral cortex of rats subjected to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Significant CINC mRNA expression was observed in the ipsilateral (ischemic) cortex from 6 h (17.3 +/- 3.7%, n = 6, P < 0.05) to 24 h (32.1 +/- 3.7%, n = 5, P < 0.01) with a peak at 12 h (43.9 +/- 3.7%, n = 6, P < 0.01) after MCAO. Five days post-MCAO, CINC mRNA levels were no longer elevated. No significant CINC mRNA expression was observed in the contralateral (control) cortex. These studies suggest that message for the neutrophil chemoattractant CINC is induced early in brain tissue subjected to ischemia, and therefore supports the possibility that brain-derived chemokines support the infiltration of circulating inflammatory cells following focal stroke.
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PMID:Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia. 815 86

Because leukocyte-mediated tissue damage is an important component of the pathologic picture in ischemia/reperfusion, we have sought mechanisms by which PMNs are directed into hypoxic tissue. Incubation of human endothelial cells (ECs) in hypoxia, PO2 approximately 14-18 Torr, led to time-dependent release of IL-8 antigen into the conditioned medium; this was accompanied by increased chemotactic activity for PMNs, blocked by antibody to IL-8. Production of IL-8 by hypoxic ECs occurred concomitantly with both increased levels of IL-8 mRNA, based on polymerase chain reaction analysis, and increased IL-8 transcription, based on nuclear run-on assays. Northern analysis of mRNA from hypoxic ECs also demonstrated increased levels of mRNA for macrophage chemotactic protein-1, another member of the chemokine superfamily of proinflammatory cytokines. IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic ECs for the NF-kB site. Studies with human umbilical vein segments exposed to hypoxia also demonstrated increased elaboration of IL-8 antigen compared with normoxic controls. In mice exposed to hypoxia (PO2 approximately 30-40 Torr), there was increased pulmonary leukostasis, as evidenced by increased myeloperoxidase activity in tissue homogenates. In parallel, increased levels of transcripts for IP-10, a murine homologue in the chemokine family related to IL-8, were observed in hypoxic lung tissue. Taken together, these data suggest that hypoxia constitutes a stimulus for leukocyte chemotaxis and tissue leukostasis.
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PMID:Hypoxic induction of interleukin-8 gene expression in human endothelial cells. 816 58

Reperfusion after ischemia induces cytokines, chemoattractant chemokines, adhesion molecules, and nitric oxide (NO). The resultant neutrophil adherence and NO potentiates renal injury. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent that inhibits neutrophil migration and production of neutrophil chemokines and NO. Since neutrophils and NO promote renal ischemic injury, we sought to determine if alpha-MSH inhibits renal injury in a model of bilateral renal ischemia. alpha-MSH significantly reduced ischemia-induced renal damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. alpha-MSH significantly decreased tubule necrosis, neutrophil plugging, and capillary congestion. Delay of alpha-MSH treatment for 6 h after ischemia also significantly inhibited renal damage. alpha-MSH also significantly inhibited ischemic damage in rats. To begin to determine the mechanism of action of alpha-MSH, we measured its effects on mediators of neutrophil trafficking and induction of the inducible isoform of NO synthase-II. alpha-MSH inhibited ischemia-induced increases in mRNA for the murine neutrophil chemokine KC/IL-8. alpha-MSH also inhibited induction of mRNA for the adhesion molecule ICAM-1, which is known to be critical in renal ischemic injury. alpha-MSH inhibited nitration of kidney proteins and induction of NO synthase-II. We conclude: (a) alpha-MSH protects against renal ischemia/reperfusion injury; and (b) it may act, in part, by inhibiting the maladaptive activation of genes that cause neutrophil activation and adhesion, and induction of NO synthase.
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PMID:Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. 907 23

Focal cerebral ischemia elicits local inflammatory reaction as demonstrated by the accumulation of inflammatory cells and mediators in the ischemic brain. Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family that possesses potent chemoattractant actions for monocytes, T cells, and smooth muscle cells. To investigate a potential role of IP-10 in focal stroke, we studied the temporal expression of IP-10 mRNA after occlusion of the middle cerebral artery in rat by means of northern analysis. IP-10 mRNA expression after focal stroke demonstrated a unique biphasic profile, with a marked increase early at 3 h (4.9-fold over control; p < 0.01), a peak level at 6 h (14.5-fold; p < 0.001) after occlusion of the middle cerebral artery, and a second wave induction 10-15 days after ischemic injury (7.2- and 9.3-fold increase for 10 and 15 days, respectively; p < 0.001). In situ hybridization confirmed the induced expression of IP-10 mRNA and revealed its spatial distribution after focal stroke. Immunohistochemical studies demonstrated the expression of IP-10 peptide in neurons (3-12 h) and astroglial cells (6 h to 15 days) of the ischemic zone. To explore further the potential role of IP-10 in focal stroke, we demonstrated a dose-dependent chemotactic action of IP-10 on C6 glial cells and enhanced attachment of rat cerebellar granule neurons. Taken together, the data suggest that ischemia induces IP-10, which may play a pleiotropic role in prolonged leukocyte recruitment, astrocyte migration/activation, and neuron attachment/sprouting after focal stroke.
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PMID:Prolonged expression of interferon-inducible protein-10 in ischemic cortex after permanent occlusion of the middle cerebral artery in rat. 972 45

Hypoxia-ischemia induces an inflammatory response in the immature central nervous system that may be important for development of brain injury. Recent data implicate that chemoattractant cytokines, chemokines, are involved in the recruitment of immune cells. The aim was to study alpha- and beta-chemokines in relation to the temporal activation of inflammatory cells after hypoxia-ischemia in immature rats. Hypoxia-ischemia was induced in 7-day-old rats (left carotid artery occlusion + 7.7% oxygen). The pups were decapitated at different times after the insult. Immunohistochemistry was used for evaluation of the inflammatory cell response and RT-PCR to analyze the cytokine mRNA and chemokine mRNA expression. A distinct interleukin-1beta and tumor necrosis factor-alpha cytokine expression was found 0-24 h after hypoxia-ischemia that was accompanied by induction of alpha-chemokines (growth related gene and macrophage inflammatory protein-2). In the next phase, the beta2-integrin expression was increased (12 h and onward) and neutrophils transiently invaded the vessels and tissue in the infarct region. The mRNA induction for the beta-chemokines macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and RANTES preceded the expression of markers for lymphocytes [cluster of differentiation (CD)4, CD8], microglia/macrophages (MHC I), and natural killer cells in the infarct area. The activation of microglia/macrophages, CD4 lymphocytes, and astroglia persisted up to at least 42 d of postnatal age implicating a chronic component of immunoinflammatory activation. The expression of mRNA for alpha- and beta-chemokines preceded the appearance of immune cells suggesting that these molecules may have a role in the inflammatory response to insults in the immature central nervous system.
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PMID:Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. 1020 41

Macrophage inflammatory protein is a member of the C-C subfamily of chemokines, which exhibits, in addition to proinflammatory activities, a potent endogenous pyrogen activity. In this study, we analysed the time-course of expression and cellular source of macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta, in inflammation of the rat brain associated with ischemia and endotoxemia. Using in situ hybridization histochemistry, we observed that intravenously injected bacterial lipopolysaccharide induced a transient expression of macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta messenger RNAs throughout the brain, with maximal expression 8-12 h after lipopolysaccharide treatment. We also revealed an early increase in macrophage inflammatory protein-1alpha and macrophage inflammatory protein-1beta messenger RNA levels, after permanent and transient middle cerebral artery occlusion, starting as early as 1 h after the occlusion and reaching a peak of expression 8-16 h after middle cerebral artery occlusion. The induction of macrophage inflammatory protein-1 messenger RNA was clearly stronger in the transient than in the permanent middle cerebral artery-occluded rat brains, showing that the reperfusion process influences the extent of the chemokine response after middle cerebral artery occlusion. In situ hybridization combined with immunohistochemistry for glial fibrillary acidic protein, a specific marker for astrocytes, excluded astrocytes as the cellular source of macrophage inflammatory protein-1 messenger RNAs after both middle cerebral artery ischemia and lipopolysaccharide treatment. Using immunohistochemistry, macrophage inflammatory protein-1alpha protein expression was shown to be induced in a time-dependent manner after lipopolysaccharide treatment and middle cerebral artery occlusion. Macrophage inflammatory protein-1alpha immunopositive cells co-localized with cells stained with OX-42 antibody, a microglia/macrophage marker. These results indicate that macrophage inflammatory protein-1 is implicated in the inflammatory reaction of the brain in response to ischemia or infection, and might modulate the host defence febrile response to a pathogenic stimulus.
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PMID:Localization of macrophage inflammatory protein: macrophage inflammatory protein-1 expression in rat brain after peripheral administration of lipopolysaccharide and focal cerebral ischemia. 1033 34

The adherence of activated neutrophils to endothelial cells during ischemia/reperfusion injury is mediated by inside-out signal transduction. Subsequently, outside-in signal transduction occurs following ligation of adhesion molecules with their ligands triggering respiratory bursts of neutrophils. In addition, neutrophil elastase enhances CC- and CXC-chemokine production by monocytes and macrophages. MCP-1, a CC-chemokine, enhances tissue factor production by macrophages and increases ICAM-1 expression on endothelial cells. Chemotaxis and respiratory bursts of neutrophils are augmented by CXC-chemokines. Furthermore, neutrophil elastase inactivates anticoagulants including antithrombin III, heparin cofactor II, and thrombomodulin, suggesting that neutrophil elastase aggravates microcirculatory disturbance after ischemia/reperfusion. Thus neutrophil elastase modulates the interation of neutrophils and endothelial cells during ischemia/reperfusion injury. Taken together with these observations, a therapeutic regimen with antibodies against adhesion molecules in combination with neutrophil elastase inhibitor and anticoagulants may attenuate ischemia/reperfusion injury.
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PMID:[Interaction between neutrophils and endothelial cells following ischemia/reperfusion]. 1041 50


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