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)

Ischemia/reperfusion (I/R) injury associated with renal transplantation may influence both early graft function and late changes. The initial (</= 7 d) events of warm and in situ perfused cold ischemia of native kidneys in uninephrectomized rats were examined. mRNA expression of the early adhesion molecule, E-selectin, peaked within 6 h; PMNs infiltrated in parallel. T cells and macrophages entered the injured kidney by 2-5 d; the associated upregulation of MHC class II antigen expression suggested increased immunogenicity of the organ. Th1 products (IL-2, TNFalpha, IFNgamma) and macrophage-associated products (IL-1, IL-6, TGFbeta) remained highly expressed after 2 d. To examine directly the effects of selectins in I/R injury, a soluble P-selectin glycoprotein ligand (sPSGL) was used. Ischemic kidneys were perfused in situ with 5 microg of sPSGL in UW solution; 50 microg was administered intravenously 3 h after reperfusion. E-selectin mRNA remained at baseline, leukocytes did not infiltrate the injured organs throughout the 7-d period, and their associated products were markedly inhibited. Class II expression did not increase. No renal dysfunction secondary to I/R occurred. The early changes of I/R injury may be prevented by treatment with soluble P- and E-selectin ligand. This may reduce subsequent host inflammatory responses after transplantation.
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PMID:The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand. 916 98

The aim of this study was to investigate the behavior of the transcription factors, heat-shock factor (HSF) and nuclear factor kappaB (NF-kappaB), in postischemic reperfused liver, with particular attention paid to possible differences in the time-course and mechanism of activation, which may help in defining their role in the response of the liver to reperfusion. Ischemia was induced by clamping the hilar pedicle of the left lateral and median liver lobes; the clamp was removed after 1 hour. Some rats were treated intraperitoneally with IL-1 receptor antagonist (IL-1RA) 30 minutes before ischemia and at the time of reperfusion. Binding of NF-kappaB to the corresponding consensus sequence is activated after 30 minutes of reperfusion, and is still increased 1 hour after reperfusion. Activation is suppressed in rats treated with IL-1RA; NF-kappaB persists in the cytosol associated with the inhibitor, IkappaB, and can be artifactually activated in vitro. Super-gel shift experiments revealed that the two subunits, p50 and p65, are involved in the activation of binding. In contrast, binding of HSF to the corresponding consensus sequence, heat shock element (HSE), is already activated at the end of ischemia, shows a further increase after 30 minutes of reperfusion, but declines 1 hour after reperfusion; more importantly, it is not inhibited by pretreatment of the rat with IL-1RA. In conclusion, although both HSF and NF-kappaB are activated by ischemia-reperfusion, there are clear differences in time-course and mechanism of activation of the two transcription factors. Activation of HSF depends directly on some events occurring during ischemia; NF-kappaB is activated only after reperfusion and the concurrent oxidative stress, by an indirect mechanism that can be suppressed by IL-1RA. The possibility of dissociating the activation of these two transcription factors in postischemic reperfusion can have a prospective clinical relevance.
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PMID:Differential activation of heat shock and nuclear factor kappaB transcription factors in postischemic reperfused rat liver. 921 68

Proinflammatory cytokines have been found to mediate part of the local and distant organ injury after ischemia and reperfusion (I/R). The anti-inflammatory cytokine interleukin-10 (IL-10) inhibits both TNF-alpha and IL-1, and we hypothesized that exogenous human IL-10 may decrease lung and soleus muscle injury after hindlimb I/R. Male Sprague-Dawley rats were randomly assigned to I/R (n = 10); I/R+IL-10 (10 micrograms i.v., n = 10), SHAM (n = 4); or SHAM+IL-10 (10 micrograms i.v., n = 4). Bilateral hindlimb ischemia was produced by tourniquet occlusion for 4 hr and all animals were sacrificed after 4 hr of reperfusion or at comparable times for the SHAMs. Soleus muscle cellular injury was determined by uptake of 99Tc pyrophosphate while soleus muscle capillary permeability, and lung capillary permeability were assessed by uptake of 125I-labeled albumin. Soleus muscle and lung neutrophil infiltration were measured with the myeloperoxidase assay. Serum samples were assessed for TNF-alpha production with the WEHI bioassay. Hindlimb I/R caused significant soleus muscle cellular injury, soleus muscle capillary injury, lung capillary injury, and lung neutrophil infiltration, Pretreatment with exogenous IL-10 significantly reduced soleus muscle capillary permeability and also reduced soleus muscle cellular injury, but not to a statistically significant degree. IL-10 administration also reduced pulmonary capillary permeability despite significantly increased lung neutrophil infiltration. Elevated TNF-alpha levels were found in 66% (4/6) rats in the I/R group versus 30% (3/10) rats in the I/R+IL-10 group. Exogenous IL-10 attenuates both local and distant organ injury after hindlimb I/R potentially independent of neutrophil infiltration.
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PMID:Exogenous human recombinant interleukin-10 attenuates hindlimb ischemia-reperfusion injury. 922 18

Subarachnoid hemorrhage (SAH) causes an inflammatory reaction and may lead to ischemic brain damage. Experimental ischemia has been shown to be connected with the alarm-reaction cytokines interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor-alpha (TNF alpha). Increased levels of these cytokines, however, have not been detected thus far in patients following an SAH event. For this reason daily cerebrospinal fluid (CSF) samples were collected from 22 consecutively enrolled patients with SAH and from 10 non-SAH patients (controls). The CSF samples were studied using immunoassays for IL-1Ra and TNF alpha to investigate whether an SAH caused increased cytokine levels. The mean IL-1Ra levels were significantly higher in patients with SAH who were in poor clinical condition on admission than in those who were in good condition (318 pg/ml vs. 82 pg/ml, p < 0.02). The IL-1Ra levels increased during delayed ischemic episodes and after surgery in patients who were in poor clinical condition. Significant increases in IL-1Ra and TNF alpha were detected during Days 4 through 10 in patients suffering from SAH who eventually had a poor outcome (p < 0.05). Patients with good outcomes and control patients had low levels of these cytokines. The levels of IL-1Ra increased after surgery in patients with Hunt and Hess Grades III through V, but not in those with Grade I or II. This finding indicates that patients in poor clinical condition have a labile biochemical state in the brain that is reflected in increased cytokine levels following the surgical trauma. Both IL-1Ra and TNF alpha are known to induce fever, malaise, leukocytosis, and nitric oxide synthesis and to mediate ischemic and traumatic brain injuries. The present study shows that levels of these cytokines increase after SAH occurs and that high cytokine levels correlate with brain damage. It is therefore likely that fever, leukocytosis, and nitric oxide synthesis are also mediated by IL-1 in patients suffering from SAH and it is probable that the inflammatory mediators contribute to brain damage.
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PMID:Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage. 925 84

The mRNA expression of the proinflammatory cytokine interleukin-1beta (IL-1beta) has been shown to be induced in neural elements during ischemia. It is not clear which cells generate the IL-1beta mRNA and eventually synthesize IL-1 protein and which cells respond to this signaling by producing IL-1 receptors during ischemia. To clarify this question, rats were subjected to global ischemia by bilateral carotid occlusion and hypotension for 20 minutes, followed by reperfusion for 2 hours (n = 7), 8 hours (n = 7), or 24 hours (n = 7). Cryostat sections were hybridized using antisense oligonucleotide probes (30 dimer). Multiple cell markers were used in immunohistochemical staining to identify the cells expressing IL-1beta and IL-1R protein. The sham animals (n = 5) showed no or only a weak expression of IL-1R or IL-1beta mRNA. The number of IL-1beta mRNA-expressing cells was significantly increased by 2 hours of reperfusion in several brain areas including cortex (12-fold compared with sham) and caudate-putamen (14-fold), and was maximally increased in most hippocampal regions by 8 hours of reperfusion (mean +/- SD of positive cells/field versus sham equivalent being 37.9 +/- 12.3 versus 4.0 +/- 3.3; 30.6 +/- 9.0 versus 3.1 +/- 2.3; 41.3 +/- 17.5 versus 2.9 +/- 1.9; in CA1; CA2; CA3/CA4 regions of the hippocampus, respectively). IL-1beta mRNA signal was also intensified in the white matter areas. Changes in IL-1R mRNA were seen in the hippocampus (after 2 hours CA1: 16-fold; CA2: 17-fold; DG: 24-fold increase; and CA3/CA4: 10-fold increase after 8 hours), and the expression was prolonged especially in CA1 and CA2 regions up to 24 hours of reperfusion. The major cellular source of IL-1beta protein was glia (astrocytes, oligodendrocytes, microglia, and scattered perivascular macrophages/monocytes), while neurons and sporadic microvascular endothelia showed IL-1R immunoreactivity. The data suggest that neurons in discrete areas vulnerable for selective neuronal death, and possibly the vascular endothelium, are target cells for ischemia-induced glial IL-1beta production.
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PMID:Global forebrain ischemia results in differential cellular expression of interleukin-1beta (IL-1beta) and its receptor at mRNA and protein level. 934 36

This review summarized evidence in support for the case that ischemia elicits an inflammatory condition in the injured brain. The inflammatory condition consists of cells (neutrophils at the onset and later monocytes) and mediators (cytokines, chemokines, others). It is clear that de novo upregulation of proinflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules in the brain follow soon after the ischemic insult and at a time when the cellular component is evolving. The significance of the inflammatory response to brain ischemia is not fully understood. Evidence is emerging in support of the possibility that the acute inflammatory reaction to brain ischemia may be causally related to brain damage. This evidence includes: 1) the capacity of cytokines to exacerbate brain damage; 2) the capacity of specific cytokine antagonists such as IL-1ra to reduce ischemic brain damage; 3) that depletion of circulating neutrophils reduces ischemic brain injury; 4) and that antagonists of the endothelial-leukocyte adhesion interactions (e.g., anti-ICAM-1) reduce ischemic brain injury. However, it should be kept in mind that cytokines were also argued to provide beneficial effects in brain injury as inferred from studies with TNF-receptor knock-out mice (p55 and p75 knock-out), which display increased sensitivity to brain ischemia, and the capacity of IL-1 to elicit the state of ischemic tolerance upon repeated administration. Nevertheless, the recent revelation on the capacity of ischemia to induce acute inflammation in the brain provides a new and fertile ground for new explorations for novel therapeutic agents that could confine the neuronal damage that follows ischemia. Furthermore, many of the genes that are upregulated by ischemia have growth-promotion capacity and therefore raise the possibility that such gene products may be useful in counteracting brain damage by enhancing repair and establishing compensatory mechanisms that enhance histological and functional recovery.
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PMID:Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. 936 86

During the ischemia/reperfusion phenomenon, adhesion molecules seem to play a critical role in the recruitment of neutrophils to sites of eventual tissue injury. E-selectin is an endothelium-derived molecule that mediates adhesion of neutrophils to activated endothelial cells. In vitro expression of E-selectin, after exposure to stimuli such as endotoxin, interleukin 1, or tumor necrosis factor alpha is maximal at 4 to 6 h, followed by a decline toward basal levels at 24 to 48 h. Characterizing the temporal expression of E-selectin in an in vivo model of skin flap ischemia-reperfusion would help to determine the optimal approach to eventual pharmacologic blockade. This intervention may prove therapeutically beneficial in attenuating flap injury. This study, using the standard porcine buttock skin flap model, was designed to evaluate immunohistochemically the expression of E-selectin in flaps subjected to (1) arterial ischemia (8 h)-reperfusion (18 h), (2) venous ischemia (8 h)-reperfusion (18 h), and (3) distal ischemia (26 h). Four flaps were examined per group, with 8 biopsies being collected sequentially over the 26-h study period from each flap. Blinded, semi-quantitative histologic scoring revealed the following results: (1) E-selectin is absent in normal porcine skin; (2) with arterial ischemia/reperfusion, E-selectin expression in flaps was maximal at 1 h of reperfusion, declining thereafter; (3) with venous ischemia/reperfusion, E-selectin expression peaked during the first hour of ischemia, with subsequent decline; and (4) within a flap designed to sustain distal ischemia, E-selectin expression is relatively more intense in regions of the flap distant from the vascular pedicle, and maximal at 6 h after flap elevation. Our conclusion, therefore, is that the kinetics of E-selectin expression within the tissues of porcine skin flaps differs depending on the type of ischemic insult sustained. Interpretation of these findings, correlating possible pathophysiologic differences in the different models of ischemia, is offered.
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PMID:Kinetics of E-selectin expression in surgical flaps. 951 61

Nitric oxide (NO) may regulate hepatic metabolism directly by causing alterations in hepatocellular (hepatocyte and Kupffer cell) metabolism and function or indirectly as a result of its vasodilator properties. Its release from the endothelium can be elicited by numerous autacoids such as histamine, vasoactive intestinal peptide, adenosine, ATP, 5-HT, substance P, bradykinin, and calcitonin gene-related peptide. In addition, NO may be released from the hepatic vascular endothelium, platelets, nerve endings, mast cells, and Kupffer cells as a response to various stimuli such as endotoxemia, ischemia-reperfusion injury, and circulatory shock. It is synthesized by nitric oxide synthase (NOS), which has three distinguishable isoforms: NOS-1 (ncNOS), a constitutive isoform originally isolated from neuronal sources; NOS-2 (iNOS), an inducible isoform that may generate large quantities of NO and may be induced in a variety of cell types throughout the body by the action of inflammatory stimuli such as tumor necrosis factor and interleukin (IL)-1 and -6; and NOS-3 (ecNOS), a constitutive isoform originally located in endothelial cells. Another basis for differentiation between the constitutive and inducible enzymes is the requirement for calcium binding to calmodulin in the former. NO is vulnerable to a plethora of biologic reactions, the most important being those involving higher nitrogen oxides (NO2-), nitrosothiol, and nitrosyl iron-cysteine complexes, the products of which (for example, peroxynitrite), are believed to be highly cytotoxic. The ability of NO to react with iron complexes renders the cytochrome P450 series of microsomal enzymes natural targets for inhibition by NO. It is believed that this mechanism provides negative feedback control of NO synthesis. In addition, NO may regulate prostaglandin synthesis because the cyclooxygenases are other hem-containing enzymes. It may also be possible that NO-induced release of IL-1 inhibits cytochrome P450 production, which ultimately renders the liver less resistant to trauma. It is believed that Kupffer cells are the main source of NO during endotoxemic shock and that selective inhibition of this stimulation may have future beneficial therapeutic implications. NO release in small quantities may be beneficial because it has been shown to decrease tumor cell growth and levels of prostaglandin E2 and F2 alpha (proinflammatory products) and to increase protein synthesis and DNA-repair enzymes in isolated hepatocytes. NO may possess both cytoprotective and cytotoxic properties depending on the amount and the isoform of NOS by which it is produced. The mechanisms by which these properties are regulated are important in the maintenance of whole body homeostasis and remain to be elucidated.
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PMID:The role of nitric oxide in hepatic metabolism. 959 11

Polymorphonuclear neutrophils (PMN) and monocytes play a role in vascular diseases. Animal experimental models, using deleukocytation or injection of anti-CD11b-anti-CD18 monoclonal antibodies (inhibition of leukocytic adhesion and of interaction with the endothelial cell) have confirmed this role in the ischemia-reperfusion syndrome and in myocardial infarction. In man, increased production of oxygen radicals, PMN release of elastase, increased monocyte formation of tissue factor (TF) and integrins have been noted in coronary artery disease, in chronic arteriopathy of the lower limbs and in association with vascular risk factors such as diabetes. Pharmacological alteration of leukocyte hyperactivity therefore seems to be justified. Pentoxifylline, used with good effect in arteriopathy of the lower limbs, affects numerous leukocytic functions: diminution in adherence and in PMN production of free radicals, diminution in the formation of TF and cytokines (TNF). Gingkolides reduce leukocytic interactions and platelet activation through an anti-PAF (Platelet Activation Factor) action. Aspirin may interfere with free radicals and inhibit TF formation. alpha-tocopherol blocks the activation, by free radicals, of the transcription factor NF k B. By altering the TNF and IL-1 cytokines, leukocytic activation can be controlled. Other cytokines (IL-4, IL-10) have an immunosuppressive action and reduce the formation of TF. The pharmacological targets are therefore multiple. Their use in vascular diseases is only at a very preliminary stage.
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PMID:[Modulators of leukocytic functions]. 960 25

The endogenous interleukin-1 receptor antagonist (IL-1ra), a protein with partial homology with the proinflammatory cytokine interleukin-1beta (IL-1beta), prevents binding of IL-1beta to the signalling receptor. Exogenous IL-1ra has been shown to reduce the neuronal damage occurring after excitotoxic amino acid administration and ischemia. In the present study, in situ hybridization histochemistry was employed to investigate the regulation of endogenous IL-1ra mRNA expression in the rat brain after peripheral administration of kainic acid (10 mg/kg). IL-1ra mRNA expression was markedly induced in the hippocampus, thalamus, amygdala, piriform cortex, perirhinal cortex, entorhinal cortex, and to a lesser extent in the hypothalamus, and parietal and temporal cortex. The expression was first detected at 5 h after the kainic acid administration and it was markedly increased at 24 h. No signal was detected at 4 days after the injection. The majority of the cells expressing IL-1ra mRNA displayed the morphological characteristics of microglia. Expression of IL-1ra mRNA in neurons occurred mainly in the piriform and perirhinal cortex. The distribution pattern of IL-1ra mRNA expressing microglia-like cells was similar to that of cells labelled with ED1, a marker for activated microglia. The induction of IL-1ra mRNA expression may represent an endogenous response to balance IL-1 receptor mediated activity in the brain following kainic acid administration, conceivably to elicit neuroprotective and/or antiinflammatory effects.
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PMID:Kainic acid induced expression of interleukin-1 receptor antagonist mRNA in the rat brain. 968 40


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