Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine exhibits potent anti-inflammatory activities but its therapeutic use is limited by cardiovascular side effects. Inhibitors of an enzyme involved in adenosine metabolism, adenosine kinase (EC 2.7.1.20), were evaluated for their ability to enhance endogenous adenosine production. One novel adenosine kinase inhibitor, GP-1-515, was studied in two models of septic shock to assess its protective effects. GP-1-515 significantly decreased mortality in mice that received a lethal i.v. injection of endotoxin. The beneficial effect was accompanied by decreased neutrophil accumulation in the lungs and was reversed by an adenosine receptor antagonist, implying that the effects were mediated by endogenous adenosine. Plasma levels of TNF-alpha, but not IL-1 alpha or IL-6, were lower in the GP-1-515-treated animals. In a second model of sepsis, GP-1-515 increased survival in bacterial peritonitis in rats. The mechanism of action in both models was likely multifactorial, including adenosine-mediated inhibition of neutrophil adhesion, cytokine production, and oxygen radical generation. Adenosine kinase inhibitors have potent anti-inflammatory effects in vitro and in vivo and represent a novel therapeutic approach to the treatment of inflammatory diseases.
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PMID:Protective effect of an adenosine kinase inhibitor in septic shock. 820 12

Endotoxin produces a variety of biological effects on different cell types, such as priming of neutrophils and macrophages, which then release a number of important mediators of endotoxin-induced lung injury. However, the specific mechanism by which endotoxin initiates its cascade of pathophysiological events in the lung has not been described. Both A1 adenosine receptor activation and endotoxin induce the release of thromboxane A2 from the lung and inhibit adenylate cyclase. By acting on A1 adenosine receptors, adenosine promotes neutrophil chemotaxis and adherence to endothelial cells. We hypothesized that A1 adenosine receptor activation is essential to endotoxin-induced lung injury, and we used the highly selective A1-adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and 8-benzyl-7,[2-[ethyl(2-hydroxyethyl)amino]-ethyl] theophylline (bamiphylline), to investigate whether selective blocking of the A1 adenosine receptor would prevent endotoxin-induced acute lung injury. An intralobar arterial infusion of endotoxin (15 mg/kg) into the left lower lobe of the lung in intact-chest, spontaneously breathing cats produced lung injury characterized by the presence of neutrophils, macrophages, and red blood cells (RBCs) in alveoli, and alveolar edema and necrosis. Lower doses of endotoxin (5 or 10 mg/kg) produced less severe and dose-dependent lung injury. Endotoxin (15 mg/kg)-induced alveolar injury was blocked in a highly significant manner by A1-adenosine receptor antagonists, DPCPX and bamiphylline. An intravenous bolus of DPCPX 30 min before endotoxin infusion or a continuous intravenous infusion of bamiphylline 30 min before, during, and 30 min after endotoxin reduced the percent injured alveoli (defined as the presence of 2 or more inflammatory cells or RBCs, or edematous fluid) from 57 +/- 31% (endotoxin 15 mg/kg) to 9 +/- 1% (DPCPX) or 21 +/- 14% (bamiphylline), which were not significantly different from control (1-h perfusion only) (4 +/- 1%) (P < 0.05). These data represent the first evidence that A1-adenosine receptor antagonism blocks the capacity of endotoxin to cause lung injury. A1-adenosine receptor antagonists may be useful in preventing adult respiratory distress syndrome associated with septicemia.
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PMID:A1-adenosine receptor antagonists block endotoxin-induced lung injury. 912 87

Sepsis induced derangements in hepatosplanchnic perfusion can contribute to organ damage and death. Adenosine, a common and potent metabolic vasodilator, has not been evaluated as a mechanism for maintenance of blood flow during sepsis. We tested the hypothesis that adenosine receptor blockade would cause a decrease in hepatosplanchnic blood flow during intraperitoneal (i.p.) sepsis in the rat. Rats (250-350 g) were catheterized for hemodynamic and blood flow measurements with tracer microspheres. Sepsis was induced with an i.p. injection of cecal material (150 mg/kg in D5W; 5 mL/kg), and baseline measurements were taken 24 h later. Animals then received either the adenosine receptor antagonist 8-PTH (10 mM, 1.5 mL/kg), its vehicle (1.5 mL/kg) or normal saline (1.5 mL/kg), intravenously, and measurements were repeated 1 and 10 min later. There was a significant increase in hepatosplanchnic portal resistance in septic animals given 8-PTH, with no change in mean arterial blood pressure (MAP) or heart rate. Regionally, there was a significant decrease in gastric, small intestinal, cecal, and pancreatic blood flow when compared with vehicle. Adenosine receptor blockade caused a significant reduction in hepatosplanchnic blood flow during sepsis, suggesting that maintenance of splanchnic blood flow during sepsis involves receptor mediated adenosine actions.
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PMID:Evidence that adenosine contributes to maintenance of hepatosplanchnic blood flow during peritoneal sepsis in rats. 918 45

By pharmacological manipulation of endogenous adenosine, using chemically distinct methods, we tested the hypothesis that endogenous adenosine tempers proinflammatory cytokine responses and oxyradical-mediated tissue damage during endotoxemia and sepsis. Rats were pretreated with varying doses of pentostatin (PNT; adenosine deaminase inhibitor) or 8-sulfophenyltheophylline (8-SPT; adenosine receptor antagonist) and then received either E. coli endotoxin (lipopolysaccharide; 0.01 or 2.0 mg/kg) or a slurry of cecal matter in 5% dextrose in water (200 mg/kg). Resultant levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-10 were measured in serum and in liver and spleen. Untreated, 2 mg/kg lipopolysaccharide elevated serum TNF-alpha, IL-1beta, and IL-10. PNT dose dependently attenuated, without ablating, the elevation in serum TNF-alpha and IL-1beta and raised liver and spleen IL-10. PNT also attenuated elevation of TNF-alpha in serum, liver, and spleen at 4 and 24 h after sepsis induction, and 8-SPT resulted in higher proinflammatory cytokines. Modulating endogenous adenosine was also effective in exacerbated (8-SPT) or diminished (PNT) tissue peroxidation. Survival from sepsis was also improved when PNT was used as a posttreatment. These data indicate that endogenous adenosine is an important modulatory component of systemic inflammatory response syndromes. These data also indicate that inhibition of adenosine deaminase may be a novel and viable therapeutic approach to managing the systemic inflammatory response syndrome without ablating important physiological functions.
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PMID:Inhibiting adenosine deaminase modulates the systemic inflammatory response syndrome in endotoxemia and sepsis. 1195 72

Sepsis is a leading cause of multiorgan dysfunction and death in hospitalized patients. Dysregulated inflammatory processes and apoptosis contribute to the pathogenesis of sepsis-induced organ dysfunction and death. A(1) adenosine receptor (A(1)AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A(1)AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A(1)AR knockout mice (A(1) knockout) and their wild-type (A(1) wild-type) littermate controls were subjected to cecal ligation and double puncture (CLP) with a 20-gauge needle. A(1) knockout mice or A(1) wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A(1)AR antagonist) had a significantly higher mortality rate compared with A(1) wild-type mice following CLP. Mice lacking endogenous A(1)ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-alpha 24 h after induction of sepsis compared with wild-type mice. The renal corticomedullary junction from A(1) knockout mice also exhibited increased myeloperoxidase activity, intercellular adhesion molecule-1 protein, and mRNA encoding proinflammatory cytokines compared with renal samples from A(1) wild-type littermate controls. No difference in renal tubular apoptosis was detected between A(1) knockout and A(1) wild-type mice. We conclude that endogenous A(1)AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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PMID:A1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis. 1578 41

The nucleoside adenosine accumulates in many tissues following the onset of ischaemia and inflammation. This initiates a series of protective mechanisms in target cells upon binding and activation of a family of four G-protein-coupled cell surface adenosine receptor (AR) proteins. The magnitude and duration of adenosine's effects are dictated by the identity and expression levels of each receptor subtype on individual cell types within the hypoxic microenvironment. Given the key role of endothelial cells (ECs) in the development of inflammatory diseases, such as sepsis, rheumatoid arthritis (RA) and atherosclerosis, ARs represent attractive targets for therapeutic intervention in these conditions. In this review, we examine several critical aspects of endothelial function in vivo, assess the role of individual AR subtypes in these events and, where known, discuss the molecular mechanisms by which specific ARs exert their effects.
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PMID:Adenosine receptors and the control of endothelial cell function in inflammatory disease. 1587 24

We recently showed that A(2A) adenosine receptor activation by endogenous adenosine contributes to interleukin-10 (IL-10) production in polymicrobial sepsis. Here we investigated the molecular mechanisms underpinning this interaction between adenosine receptor signaling and infection by exposing macrophages to Escherichia coli. We demonstrated using receptor knockout mice that A(2A) receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production by E coli-challenged macrophages, whereas A(2B) receptors have a minor role. The stimulatory effect of adenosine on E coli-induced IL-10 production did not require toll-like receptor 4 (TLR4) or MyD88, but was blocked by p38 inhibition. Using shRNA we demonstrated that TRAF6 impairs the potentiating effect of adenosine. Measuring IL-10 mRNA abundance and transfection with an IL-10 promoter-luciferase construct indicated that E coli and adenosine synergistically activate IL-10 transcription. Sequential deletion analysis and site-directed mutagenesis of the IL-10 promoter revealed that a region harboring C/EBP binding elements was responsible for the stimulatory effect of adenosine on E coli-induced IL-10 promoter activity. Adenosine augmented E coli-induced nuclear accumulation and DNA binding of C/EBPbeta. C/EBPbeta-deficient macrophages failed to produce IL-10 in response to adenosine and E coli. Our results suggest that the A(2A) receptor-C/EBPbeta axis is critical for IL-10 production after bacterial infection.
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PMID:A2A adenosine receptors and C/EBPbeta are crucially required for IL-10 production by macrophages exposed to Escherichia coli. 1752 87

A key step in the pathogenesis of sepsis is the excessive and uncontrolled activation of polymorphonuclear neutrophils (PMNs). An inflammation-controlling function of adenosine receptors has been presumed; however, their role in PMN of sepsis patients is poorly defined. We investigated the expression of adenosine receptors in resting and lipopolysaccharide (LPS) -activated human PMNs, and in PMNs of sepsis patients. Our studies revealed that native human PMNs express almost equal distributions of all four adenosine receptor subtype transcripts, whereas exclusively the A(2A) receptor (A(2A)R) was up-regulated in LPS-stimulated PMNs and PMNs of sepsis patients. As a possible mechanism, we identified and fully characterized eight 5'-untranslated region (UTR) splice variants of the A(2A)R gene resulting from alternative transcription and/or splicing of five noncoding exons. We report a differential, activation state-specific expression of 5'-UTR variants within the same cell type, indicating a new mechanism to modulate gene expression: In resting human PMNs, mainly A(2A)R transcripts with long 5'-UTRs are expressed, whereas in stimulated PMNs and PMNs of septic patients, short 5'-UTRs predominate. Transcripts with short 5'-UTRs are more efficiently translated into protein. The correlation between changes of transcript patterns and A(2A)R up-regulation offers interesting clues regarding the course of sepsis.
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PMID:Differential expression of 5'-UTR splice variants of the adenosine A2A receptor gene in human granulocytes: identification, characterization, and functional impact on activation. 1854 93

Adenosine is a purine nucleoside, which is produced inside the body under metabolic stress like hypoxic conditions, acute or chronic inflammatory tissue insults. The synthesis of adenosine involves the catabolism of adenine nucleotides (ATP, ADP and AMP) by the action of extracellular ectonucleotidases i.e. CD39 or nucleoside triphosphate dephosphorylase (NTPD) and CD73 or 5'-ectonucleotidase. Once adenosine is released in the extracellular environment, it binds to different types of adenosine (i.e. adenosine A(1), A(2A), A(2B) and A(3) receptors) receptors expressed on various innate immune cells [Neutrophils, macrophages, mast cells, dendritic cells and natural killer cells]. Thus, depending on the type of adenosine receptor to which it binds, adenosine modulates innate immune response during various inflammatory conditions [i.e. chronic (cancer, asthma) as well as acute (sepsis, acute lung injury) inflammatory diseases]. This review summarizes the effect of adenosine on innate immunity and the use of adenosine receptor specific agonists or antagonists in various immunologic disorders (asthma, cancer, HIV-1 infection) as future immunomodulatory therapeutics.
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PMID:Adenosine: an endogenous modulator of innate immune system with therapeutic potential. 1946 86

The study of the A(3) adenosine receptor (A(3)AR) represents a rapidly growing and intense area of research in the adenosine field. The present chapter will provide an overview of the expression patterns, molecular pharmacology and functional role of this A(3)AR subtype under pathophysiological conditions. Through studies utilizing selective A(3)AR agonists and antagonists, or A(3)AR knockout mice, it is now clear that this receptor plays a critical role in the modulation of ischemic diseases as well as in inflammatory and autoimmune pathologies. Therefore, the potential therapeutic use of agonists and antagonists will also be described. The discussion will principally address the use of such compounds in the treatment of brain and heart ischemia, asthma, sepsis and glaucoma. The final part concentrates on the molecular basis of A(3)ARs in autoimmune diseases such as rheumatoid arthritis, and includes a description of clinical trials with the selective agonist CF101. Based on this chapter, it is evident that continued research to discover agonists and antagonists for the A(3)AR subtype is warranted.
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PMID:A3 adenosine receptor: pharmacology and role in disease. 1963 86


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