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 examined the effects of early blockade of CD62 selectin-mediated adhesive interactions in steatotic rat liver models of ex vivo cold ischemia followed by reperfusion or transplantation by administration of P-selectin glycoprotein ligand-1 (rPSGL-Ig). In the model of cold ischemia/reperfusion, livers pretreated ex vivo with rPSGL-Ig at harvesting from obese Zucker rats showed significantly decreased portal resistance, increased bile production, and diminished hepatic endothelial neutrophil infiltration, as compared with untreated controls. Pretreatment of fatty livers with rPSGL-Ig prior to transplantation extended the survival of lean Zucker rat recipients from 40% to 90%. This effect correlated with significantly improved liver function, depressed neutrophil activity, and decreased histologic features of hepatocyte injury. Intragraft expression of CD62 P-selectin was similar in both recipient groups. rPSGL-Ig treatment decreased intragraft infiltration by CD3/CD25 cells, diminished expression of pro-inflammatory TNFalpha, IL-6, iNOS, IL-2 and IFN-gamma, without significantly affecting mRNA levels coding for anti-inflammatory IL-4. Thus, rPSGL-Ig blockade of CD62-mediated adhesive interactions protects against severe ischemia/reperfusion injury suffered otherwise by steatotic rat livers. These findings document the potential utility of rPSGL-Ig in increasing the transplant donor pool through modulation of marginal steatotic livers.
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PMID:P-selectin glycoprotein ligand-1 (rPSGL-Ig)-mediated blockade of CD62 selectin molecules protects rat steatotic liver grafts from ischemia/reperfusion injury. 1220 60

Ischemia-reperfusion brain injury initiates an inflammatory response involving the expression of adhesion molecules and cytokines, some of which are regulated by the nuclear transcription factor NF-kappaB. In this study the authors examined mRNA expression levels for several important genes associated with inflammation at five time points (3, 6, 12, 24, and 72 hours) after transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. A sensitive and quantitative technique (TaqMan real-time QRT-PCR) was used to simultaneously measure mRNA levels for key cell adhesion molecules and inflammatory cytokines. Gene expression increased significantly in the injured hemisphere for interleukin (IL)-1beta (12-fold increase at 24 hours), IL-6 (25-fold increase at 6 hours) and ICAM-1 (4-fold increase at 24 hours), and the interhemispheric differences for these genes were significant for every time point examined (P < 0.05 for all values). Tumor necrosis factor-alpha mRNA was upregulated in the injured versus uninjured hemisphere from 3 to 24 hours (5-fold increase at 6 hours), while E-selectin showed a significant increase in mRNA levels from 6 to 24 hours after MCAO (10-fold increase at 6 hours) (P < 0.05 for all values). VCAM-1 mRNA levels did not respond differentially to injury at any time point between the two brain hemispheres. At all time points examined, activated NF-kappaB immunoreactivity was observed in cells throughout the infarct-damaged tissue. These results are consistent with the proinflammatory properties of the induced molecules, which are involved in the initiation of the inflammatory cascade, and may thus contribute to secondary cellular responses that lead to further brain damage.
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PMID:Quantitative real-time RT-PCR analysis of inflammatory gene expression associated with ischemia-reperfusion brain injury. 1221 12

Today, the major problem in organ transplantation is not acute graft rejection but chronic graft deterioration. In addition to alloantigen-specific events, alloantigen independent factors like donor age, previous diseases, consequences of brain death, and perioperative events of ischemia/reperfusion injury have a major impact on long-term graft function. The induction of the stress protein heme oxygenase-1 (HO-1) protects cells from injury and apoptosis. Here, we tested the protective effects of HO-1 induction in a clinically relevant kidney transplant model. Induction of HO-1 expression following cobalt-protoporphyrin (CoPP) treatment in organ donors prolonged graft survival and long-term function remarkably following extended periods of ischemia. Positive effects were observed with both optimal and marginal grafts from old donor animals. Structural changes characteristic for chronic rejection, as well as graft infiltration by monocytes/macrophages and CD8+ T cells, were substantially reduced following HO-1 induction. Up-regulation of HO-1 expression before organ transplantation was also associated with reduced levels for tumor necrosis factor (TNF)-alpha mRNA, increased levels for interferon (IFN)-gamma, and bcl-x, and insignificant differences for CD25, interleukin (IL)-2, IL-4, IL-6, and IL-10 mRNA levels. The significant improvement of long-term graft function following induction of HO-1 expression in donor organs suggests that this strategy may be a novel clinical treatment option with particular relevance for transplantation of marginal organs.
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PMID:Inhibition of ischemia/reperfusion injury and chronic graft deterioration by a single-donor treatment with cobalt-protoporphyrin for the induction of heme oxygenase-1. 1235 73

Inflammatory cytokines interleukin 1 (IL-1), IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha) have been recognized as important mediators of pathophysiological and immunological events associated with shock. These inflammatory events after hemorrhage and resuscitation are characterized by the activation of transcription regulators such as nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Curcumin, an anti-inflammatory remedy used in Indian medicine, is known to suppress NF-kappaB and AP-1 activation and also to reduce ischemia-reperfusion injuries in animal models. Therefore, the aim of this study was to determine whether administration of curcumin before hemorrhagic shock has any salutary effects on cytokines and the redox-sensitive transcription factors NF-kappaB and AP-1. mRNA levels of IL-1alpha, IL-1beta, IL-2, IL-6, IL-10, and TNF-alpha were determined by reverse transcriptase-polymerase chain reaction in rat livers collected at 2 and 24 h after hemorrhage/resuscitation. The effect of curcumin on the activation of NF-kappaB and AP-1 was determined by electrophoretic mobility shift assays. Significant increases in the levels of liver cytokines IL-1alpha, IL-1beta, IL-2, IL-6, and IL-10 were observed in the 2-h posthemorrhage/resuscitation group compared with sham animals. In contrast, oral administration of curcumin for 7 days followed by hemorrhage/resuscitation regimen resulted in significant restoration of these cytokines to depleted levels, and, in fact, IL-1beta levels were lower than sham levels. Also, the 24-h postresuscitation group showed similar patterns with some exceptions. NF-kappaB and AP-1 were differentially activated at 2 and 24 h posthemorrhage and were inhibited by curcumin pretreatment. Serum aspartate transaminase estimates indicate decreased liver injury in curcumin-pretreated hemorrhage animals. These results suggest that protection against hemorrhage/resuscitation injury by curcumin pretreatment may result from the inactivation of transcription factors involved and regulation of cytokines to beneficial levels.
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PMID:Differential regulation of cytokines and transcription factors in liver by curcumin following hemorrhage/resuscitation. 1257 24

Acute renal failure (ARF) commonly occurs after whole body ischemia. Most experimental models of ARF have relied on the isolated renal artery clamping model; however, there is a pressing need to develop and understand the pathogenesis of new models with more "clinical relevance." We evaluated a new murine model of ARF after whole body ischemia reperfusion injury (WBIRI). WBIRI was induced by an infusion of potassium chloride and a cardiac arrest period of 10 min. Resuscitation was achieved by cardiac compressions, ventilation, epinephrine, and fluids. WBIRI leads to a significant increase in serum creatinine (SCr) and renal tubular injury by 24 h. Renal myeloperoxidase (MPO) levels increased at 24 h after WBIRI. Increased expression of the proinflammatory genes, ICAM-1 and IL-6, was also observed in the kidney following WBIRI. On the basis of recent data that T cells are important mediators of isolated renal IRI, WBIRI was evaluated in T cell-deficient nu/nu mice. T cell-deficient mice had a significantly reduced rise in SCr and decreased tubular injury compared with wild-type mice. T cell-deficient mice had a decrease in ICAM-1 expression after WBIRI, but no decrease in renal MPO. This study describes a new, clinically relevant, model of ARF after WBIRI in mice and identifies the T cell as an important mediator of renal injury following WBIRI. Reduced ICAM-1 expression may provide a mechanism for this involvement.
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PMID:Acute renal failure after whole body ischemia is characterized by inflammation and T cell-mediated injury. 1265 60

Chitosan is widely used to treat patients with hypoxia-induced diseases such as ischemia, neuronal death, cerebral stroke, and cerebral infarction. Using the ELISA method, we examined the effect of high molecular weight water-soluble chitosan (WSC) on inflammatory cytokine production in the desferrioxamine (DFX, known to mimic hypoxia)-stimulated human mast cell line HMC-1. DFX significantly increased interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha production compared with the control in a time-dependent manner (p<0.05), but did not affect IL-1alpha production and mRNA expression. The increase in IL-6, IL-8, and TNF-alpha levels was significantly inhibited by WSC in a dose-dependent manner with IC(50) values of 0.77, 0.88, and 2.5 microg/ml, respectively. The maximal inhibition rate of IL-6, IL-8, and TNF-alpha production by WSC was 64+/-9.7%, 80+/-9.4% and 54+/-4.5%, respectively. In addition, WSC inhibited DFX-induced activation of nuclear factor (NF)-kappaB. In conclusion, these results suggest that WSC is an inhibitor of NF-kappaB under hypoxic conditions, which might explain its beneficial effect in the treatment of hypoxia-induced inflammatory diseases.
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PMID:Inhibitory effect of high molecular weight water-soluble chitosan on hypoxia-induced inflammatory cytokine production. 1273 19

The anti-inflammatory cytokine interleukin (IL)-10 has been detected in serum after visceral ischemia-reperfusion injury and exogenous IL-10 administration has been shown to attenuate the associated distant organ injury. This study was designed to examine the role that endogenous IL-10 production plays on both local and distant organ injury after visceral ischemia-reperfusion injury. Wild-type and IL-10(-/-)-null C57BL/6 mice were subjected to 20 min of supraceliac aortic occlusion or sham laparotomy. Serum and lung tissue cytokine levels (tumor necrosis factor alpha, IL-1beta, IL-6, KC/GRO, and IL-10) were measured after reperfusion (1, 2, and/or 4 h) using either enzyme-linked immunoassay or bioassay. Lung neutrophil infiltration and injury were quantified after reperfusion injury using myeloperoxidase concentration (2 h) and mean capillary permeability (4 h), respectively, whereas the direct liver injury was quantified with serum aspartate aminotransferase levels (1, 2, and 4 h). A subset of IL-10(-/-)-null animals was administered human recombinant IL-10 before the visceral ischemia and lung MPO was measured after reperfusion (2 h). Visceral ischemia-reperfusion in the wild-type and IL-10(-/-)-null mice was associated with in an increase in both serum (IL-1beta, KC/GRO, IL-6) and lung tissue (IL-1beta, KC/GRO) cytokine levels and resulted in lung neutrophil infiltration (myeloperoxidase), lung injury (mean capillary permeability) and liver injury (aspartate aminotransferase). The magnitude of the lung tissue cytokine response (IL-1beta, KC/GRO), neutrophil infiltration, and injury were greater in the IL-10(-/-)-null mice. Exogenous IL-10 resulted in a decrease in the lung neutrophil infiltration in the IL-10(-/-)-null mice. The endogenous IL-10 response to visceral ischemia-reperfusion attenuates the associated lung neutrophil infiltration and injury but has no effect upon either the hepatic injury or the magnitude of the systemic inflammatory response. The beneficial effects of IL-10 may be mediated by the inhibition of IL-1beta and KC/GRO through an endocrine rather than paracrine signal.
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PMID:Role of endogenous interleukin-10 in local and distant organ injury after visceral ischemia-reperfusion. 1281 66

Burn trauma produces significant fluid shifts that, in turn, reduce cardiac output and tissue perfusion. Treatment approaches to major burn injury include administration of crystalloid solutions to correct hypovolemia and to restore peripheral perfusion. While this aggressive postburn volume replacement increases oxygen delivery to previously ischemic tissue, this restoration of oxygen delivery is thought to initiate a series of deleterious events that exacerbate ischemia-related tissue injury. While persistent hypoperfusion after burn trauma would produce cell death, volume resuscitation may exacerbate the tissue injury that occurred during low flow state. It is clear that after burn trauma, tissue adenosine triphosphate (ATP) levels gradually fall, and increased adenosine monophosphate (AMP) is converted to hypoxanthine, providing substrate for xanthine oxidase. These complicated reactions produce hydrogen peroxide and superoxide, clearly recognized deleterious free radicals. In addition to xanthine oxidase related free radical generation in burn trauma, adherent-activated neutrophils produce additional free radicals. Enhanced free radical production is paralleled by impaired antioxidant mechanisms; as indicated by burn-related decreases in superoxide dismutase, catalase, glutathione, alpha tocopherol, and ascorbic acid levels. Burn related upregulation of inducible nitric oxide synthase (iNOS) may produce peripheral vasodilatation, upregulate the transcription factor nuclear factor kappa B (NF-kappaB), and promote transcription and translation of numerous inflammatory cytokines. NO may also interact with the superoxide radical to yield peroxynitrite, a highly reactive mediator of tissue injury. Free radical mediated cell injury has been supported by postburn increases in systemic and tissue levels of lipid peroxidation products such as conjugated dienes, thiobarbituric acid reaction products, or malondialdehyde (MDA) levels. Antioxidant therapy in burn therapy (ascorbic acid, glutathione, N-acetyl-L-cysteine, or vitamins A, E, and C alone or in combination) have been shown to reduce burn and burn/sepsis mediated mortality, to attenuate changes in cellular energetics, to protect microvascular circulation, reduce tissue lipid peroxidation, improve cardiac output, and to reduce the volume of required fluid resuscitation. Antioxidant vitamin therapy with fluid resuscitation has also been shown to prevent burn related cardiac NF-kappaB nuclear migration, to inhibit cardiomyocyte secretion of TNF-alpha, IL-1beta, and IL-6, and to improve cardiac contractile function. These data collectively support the hypothesis that cellular oxidative stress is a critical step in burn-mediated injury, and suggest that antioxidant strategies designed to either inhibit free radical formation or to scavage free radicals may provide organ protection in patients with burn injury.
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PMID:Free radicals and lipid peroxidation mediated injury in burn trauma: the role of antioxidant therapy. 1282 Dec 84

Loss of blood-brain barrier (BBB) function may contribute to post-ischemic cerebral injury by yet unknown mechanisms. Ischemia is associated with anoxia, aglycemia and loss of flow (i.e. shearing forces). We tested the hypothesis that loss of shear stress alone does not acutely affect BBB function due to a protective cascade of mechanisms involving cytokines and nitric oxide (NO). To determine the relative contribution of shear stress on BBB integrity we used a dynamic in vitro BBB model based on co-culture of rat brain microvascular endothelial cells (RBMEC) and astrocytes. Trans-endothelial electrical resistance (TEER), IL-6 release and NO levels were measured from the lumenal and ablumenal compartments throughout the experiment. Flow-exposed RBMEC were challenged with 1 h of normoxic-normoglycemic flow cessation (NNFC) followed by reperfusion for 2 to 24 h. NNFC caused a progressive drop in nitric oxide production during flow cessation followed by a time-dependent increase in ablumenal IL-6 associated with a prolonged NO increase during reperfusion. The nitric oxide synthetase (NOS) inhibitor L-NAME (10 microM) abrogated all effects of NNFC, including changes in NO and cytokine production. BBB permeability did not increase during or after NNFC/reperfusion, but was increased by treatment with L-NAME or when the effects of IL-6 were blocked. Flow adapted RBMEC and astrocytes respond to NNFC/reperfusion by overproduction of IL-6, possibly secondary to increased production of NO during the reperfusion. Maintenance of BBB function during and following NNFC appears to depend on intact NO signaling and IL-6 release.
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PMID:Effects of transient loss of shear stress on blood-brain barrier endothelium: role of nitric oxide and IL-6. 1283 84

Nitric oxide synthase (NOS) expressions in skeletal muscle subjected to ischemia/reperfusion (I/R) were studied using a hind limb tourniquet ischemia model in mice. A rubber band was applied to a hind limb for 3 h under isoflurane anesthesia followed by 1 or 4 h of reperfusion. Increased NADPH diaphorase activity and NOS immunoreactivity were histochemically detected in the cells of muscle that had been subjected to I/R. The results of RT-PCR of the muscle subjected to I/R showed that NOS mRNA expressions were not significantly increased until 4 h after the start of reperfusion. Since there was no significant difference between histochemical findings or between water contents of the hind limbs or organs in interleukin (IL)-6-deficient mice and the wild-type mice, IL-6 may not be involved in the early stage of I/R muscle injury such as that in this model. O(2)(-) production in the cells of muscle that had been subjected to I/R was observed using an in situ detection method with hydroethidine, and the O(2)(-) was inhibited by intravenous administration of L-NAME or L-NMMA, but not L-NIL, 30 min before tourniquet release. Further study is needed to evaluate the role of O(2)(-) produced by constitutive NOS in muscle subjected to I/R in the pathophysiology of tourniquet shock.
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PMID:Nitric oxide synthase expressions in mice skeletal muscle subjected to ischemia/reperfusion injury. 1293 94


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