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)

Studies were undertaken to define the role of 5-lipoxygenase (5-LO) products and, in particular, of leukotriene (LT) B4 in the polymorphonuclear leukocyte (PMN) emigration process using a rabbit model of dermal inflammation. Our results show that i.v. administration to rabbits of MK-0591, a compound that inhibits LT biosynthesis in blood and tissues when administered in vivo, significantly reduced 51Cr-labeled PMN accumulation in response to intradermally injected chemotactic agonists, including IL-8, FMLP, C5a, and LTB4 itself. In addition, pretreatment of the labeled PMN with MK-0591 ex vivo before their injection in recipient animals was equally effective in reducing 51Cr-labeled PMN emigration to dermal inflammatory sites. These results support a role for de novo synthesis of 5-LO metabolites by PMN for their chemotactic response to inflammatory mediators. Other studies demonstrated that elevated intravascular concentration of LTB4 interferes with PMN extravasation inasmuch as a continuous i.v. infusion of LTB4, in the range of 5-300 ng/min/kg, dose-dependently inhibited extravascular PMN accumulation to acute inflammatory skin sites elicited by the chemoattractants LTB4, FMLP, C5a, and IL-8 and by TNF-alpha, IL-1beta, and LPS; such phenomena may constitute a natural protective mechanism from massive tissue invasion by activated PMN in specific pathologic conditions such as ischemia (and reperfusion). These studies demonstrate additional functions of 5-LO products in the regulation of PMN trafficking, distinct from the well-characterized chemotactic activity of LTB4 present in the extravascular compartment.
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PMID:Role of 5-lipoxygenase products in the local accumulation of neutrophils in dermal inflammation in the rabbit. 1047 17

Cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha can play pathogenetic or protective roles in stroke. They are increased in the brain after experimental ischemia and in the CSF of patients with stroke. However, their presence in the periphery is still controversial. To determine the source and time-course of cytokines in blood of stroke patients, IL-6 and TNF-alpha release from blood cells and serum levels were determined in 40 patients on days 1 through 2, 4, 10, 30, and 90 after stroke. Twenty healthy age-matched volunteers were used as controls. IL-6 and TNF-alpha release from stimulated blood cells was increased in stroke patients, compared to controls. A peak response (+224%) was observed at day 4 for IL-6, while TNF-alpha release was largely and significantly increased (about three-fold compared to controls) from day 1 to 2 until day 90 after stroke. The increase in IL-6 release was significantly higher in ischemic, compared to hemorrhagic strokes, at days 1 and 4. Circulating IL-6 was increased at each time point. The ischemic processes in the CNS induces a long-lasting activation of IL-6 and TNF-alpha production in peripheral blood cells, which are a major source of serum cytokines after stroke.
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PMID:Increased cytokine release from peripheral blood cells after acute stroke. 1047 52

The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.
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PMID:Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. 1049 Sep 98

We evaluated the proinflammatory cytokines, TNF-alpha and IL-1beta, mRNA expression in the rat sciatic and tibial nerves following ischemia-reperfusion (IR) injury, using competitive RT-PCR, to explore the role of cytokines in IR injury. The expressions of both TNF-alpha and IL-1beta mRNA were related to severity of ischemia and occurred with reperfusion rather than ischemia alone. TNF-alpha gene expression peaked at 24 h of reperfusion, while that of IL-1beta peaked at 12 h. These data support the notion that the proinflammatory cytokines TNF-alpha and IL-1beta are involved in the inflammatory response of IR injury to the peripheral nervous system and may be involved in the pathophysiology of ischemic fiber degeneration.
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PMID:The expression of proinflammatory cytokine mRNA in the sciatic-tibial nerve of ischemia-reperfusion injury. 1053 76

Shock is a biological response associated with hypotension and signs of altered tissue perfusion. Shock can be induced by many different mechanisms. Shock itself induces cytokine production as a result of disturbed microcirculation or ischemia-reperfusion injury. Alternatively, severe inflammatory conditions, such as sepsis and severe acute pancreatitis, are usually associated with prominent mediator production, which often leads to shock. TNF-alpha and IL-1 beta increase the vascular permeability, and nitric oxide reduces systemic vascular resistance. In the management of patients who have experienced clinical insult, we must consider the symptoms of systemic inflammatory response syndrome provoked by inflammatory mediators as a warning sign of the development of shock and organ dysfunction. Early withdrawal from SIRS and avoidance of infectious complications (second attack) should be attempted.
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PMID:[Shock and its mediators]. 1057 Jul 77

IL-1 and TNF-alpha are known to be pleiotropic cytokines associated with various inflammatory conditions such as small intestinal injury after ischemia-reperfusion. FR167653 has been characterized as a potent suppressant of IL-1 and TNF-alpha production. The effect of FR167653 on intestinal reperfusion injury was investigated in a warm ischemia model of the canine gut. Sixteen mongrel dogs were divided into two groups: a control group and a FR group to which FR167653 was administered. Both the superior mesenteric artery and vein were clamped for 2 hr. Arterial pH, hepatic venous hemoglobin oxygen saturation, intramucosal pH, and the survival rate were well maintained in the FR group in comparison with the control group after reperfusion. FR167653 inhibited the expression of IL-1beta mRNA. Histologically, ischemia-reperfusion injury was more severe in the control group than the FR group. This study suggests that FR167653 inhibits proinflammatory cytokines and ameliorates ischemia-reperfusion injury of the small intestine.
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PMID:Effect of FR167653 on small bowel ischemia-reperfusion injury in dogs. 1057 84

In vivo administration of low doses of lipopolysaccharide (LPS) to rodents can protect these animals from subsequently administrated, usually lethal doses of endotoxin or LPS. In this study we tested the effects of LPS pretreatment on ischemia/reperfusion injury in the kidney. Male C57/B1 mice were pretreated with different doses of LPS or phosphate-buffered saline on days -4 and -3. The right kidney was removed, and the vessels of the left kidney were clamped for 30 or 45 minutes on day 0. Creatinine levels and survival of animals were monitored. To test the involvement of cytokines, additional animals were harvested before ("time 0") and 15 minutes, 1, 2, 8, and 16 hours after reperfusion for histology, immunohistochemistry, terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay, and reverse transcriptase-polymerase chain reaction analysis (including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, inducible nitric oxide synthase (iNOS), and interferon (IFN)-gamma messenger RNA (mRNA)). In controls, renal ischemia of 30 minutes was nonlethal, whereas 73% of the animals died within 48 +/- 18 hours, after 45 minutes of ischemia. All different doses of LPS protected the animals from lethal renal ischemia/reperfusion injury. Starting at similar levels, serum creatinine increased significantly in controls but not in LPS-pretreated animals over time. As early as 2 hours after reperfusion, tubular cell damage was significantly more pronounced in controls than in LPS-treated mice. In controls, tubules deteriorated progressively until 8 hours of reperfusion. At this time, more than 50% of tubular cells were destroyed. This destruction was accompanied by a pronounced leukocytic infiltration, predominantly by macrophages. In contrast, LPS pretreatment prevented the destruction of kidney tissue and infiltration by leukocytes. The terminal deoxynucleotidyltransferase-mediated UTP end-labeling assay revealed significantly more apoptotic cells in controls compared with LPS-pretreated animals. IL-1, IFN-gamma, and iNOS mRNA expression did not differ between the groups throughout the time points examined. However, the expression of TNF-alpha mRNA was significantly increased at 2 hours and IL-6 mRNA was significantly down-regulated before ischemia and shortly after reperfusion in the LPS-pretreated kidneys. Therefore, we found that sublethal doses of LPS induced cross-tolerance to renal ischemia/reperfusion injury. Our data suggest that increased TNF-alpha and reduced IL-6 mRNA expression might be responsible. However, more studies are needed to decipher the exact mechanism.
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PMID:Lipopolysaccharide pretreatment protects from renal ischemia/reperfusion injury : possible connection to an interleukin-6-dependent pathway. 1062 77

Extracellular purines, including adenosine and ATP, are potent endogenous immunomodulatory molecules. Inosine, a degradation product of these purines, can reach high concentrations in the extracellular space under conditions associated with cellular metabolic stress such as inflammation or ischemia. In the present study, we investigated whether extracellular inosine can affect inflammatory/immune processes. In immunostimulated macrophages and spleen cells, inosine potently inhibited the production of the proinflammatory cytokines TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1alpha, and IFN-gamma, but failed to alter the production of the anti-inflammatory cytokine IL-10. The effect of inosine did not require cellular uptake by nucleoside transporters and was partially reversed by blockade of adenosine A1 and A2 receptors. Inosine inhibited cytokine production by a posttranscriptional mechanism. The activity of inosine was independent of activation of the p38 and p42/p44 mitogen-activated protein kinases, the phosphorylation of the c-Jun terminal kinase, the degradation of inhibitory factor kappaB, and elevation of intracellular cAMP. Inosine suppressed proinflammatory cytokine production and mortality in a mouse endotoxemic model. Taken together, inosine has multiple anti-inflammatory effects. These findings, coupled with the fact that inosine has very low toxicity, suggest that this agent may be useful in the treatment of inflammatory/ischemic diseases.
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PMID:Inosine inhibits inflammatory cytokine production by a posttranscriptional mechanism and protects against endotoxin-induced shock. 1062 51

To examine whether adenosine reduces ischemia/reperfusion (I/R)-induced liver injury by inhibiting leukocyte activation via A2 receptor (A2R), we investigated the effects of adenosine and YT-146, selective A2A receptor (A2AR) agonist, on I/R-induced liver injury in rats. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil elastase release from isolated neutrophils by about 35% in vitro. Adenosine and YT-146, in the range of concentrations of 10(-7)-10(-5) M, significantly inhibited the endotoxin-stimulated TNF-alpha production by monocytes to less than 50% of the control. Although ZM241385, a selective A2AR antagonist, significantly enhanced the fMLP-induced neutrophil elastase release in isolated neutrophils in vitro, this agent did not affect the endotoxin-stimulated TNF-alpha production by monocytes. Male Wistar rats were subjected to complete ischemia of median and left lobes of liver for 60 min and the subsequent reperfusion. Serum levels of transaminases increased over time after hepatic I/R, peaking at 12 hrs after reperfusion. Intravenous infusion of Adenosine (1 and 10 mg/kg/hr) and YT-146 (0.1 and 1 mg/kg/hr) significantly inhibited the I/R-induced increases in serum transaminase levels 12 hrs after reperfusion. The I/R-induced decrease in hepatic tissue blood flow was significantly inhibited by adenosine and YT-146. Hepatic levels of TNF-alpha, cytokine-induced neutrophil chemoattractant (a member of interleukin-8), and myeloperoxidase were significantly increased after I/R. These increases were significantly inhibited by administration of adenosine and YT-146. However, ZM241385 did not reduce the I/R-induced liver injury and it inhibited neither the decrease in hepatic tissue blood flow, nor the indicators of leukocyte activation. These findings suggest that adenosine may reduce I/R-induced liver injury mainly by inhibiting hepatic TNF-alpha production via A2AR, thereby reducing neutrophil activation.
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PMID:[Adenosine reduces ischemia/reperfusion-induced liver injury by inhibiting leukocyte activation]. 1062 74

Although neutrophils have been implicated in the hepatic injury elicited by gut ischemia/reperfusion (I/R), the contribution of other leukocyte populations to this injury process remains unclear. The objective of this study was to determine whether lymphocytes contribute to gut I/R-induced microvascular dysfunction and inflammatory responses in the liver. Intravital videomicroscopy was used to monitor leukocyte recruitment, the number of nonperfused sinusoids and pyridine nucleotide (NADH) autofluorescence in livers of wild-type, SCID, and interferon-gamma (IFN-gamma) knockout mice exposed to 15 min of gut ischemia and 1 h of reperfusion. In wild-type mice, gut I/R elicited significant increases in the number of stationary leukocytes, nonperfused sinusoids, NADH autofluorescence (indicating hypoxia), and elevated plasma alanine aminotransferase (ALT) and TNF-alpha levels. All of these responses were profoundly attenuated in SCID mice, while only some of the responses (in the midzonal region) were blunted in IFN-gamma knockout mice. Reconstitution (24 h before ischemia) of the circulating lymphocyte pool with T-cell enriched splenocytes, but not T cell deficient (from nude mice), CD4+ T-cell depleted splenocytes or splenocytes derived from IFN-gamma knockout mice, allowed the SCID mice to respond to gut I/R in a manner similar to wild-type mice. Some of the responses were restored following reconstitution with CD8+ T-cell depleted splenocytes. These findings implicate CD4+ T-lymphocytes and IFN-gamma in the hepatic microvascular dysfunction and inflammatory cell accumulation elicited by gut I/R.
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PMID:T-lymphocytes contribute to hepatic leukostasis and hypoxic stress induced by gut ischemia-reperfusion. 1065 78


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