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

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.
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PMID:The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity. 870 44

As the mechanism of ischemic preconditioning unfolds, various strategies for inducing pharmacologic preconditioning become apparent. Adenosine receptor agonists, KATP channel activators, and endothelial-neutrophil adhesion antagonists have enjoyed cardioprotective activity against ischemia/reperfusion injury in at least some preclinical models. Monophosphoryl lipid A (MLA), a structural derivative of the pharmacophore of endotoxin, enjoys an improved therapeutic index in relation to the parent biological product. MLA has found clinical application as a vaccine adjuvant and protects from sepsis and septic shock in the preclinical setting. In animal models of myocardial ischemia/reperfusion injury, pretreatment 12-24 hours prior to ischemia with a single IV bolus injection of MLA limits infarct size 50 to 75 percent in standard canine and rabbit models at doses of 10-35 micrograms/kg. Regional myocardial stunning following multiple 5-minute ischemic episodes as assessed by segment shortening is reduced in dogs pretreated 24 but not 1 hour prior to ischemia. Global cardiac function, as evaluated by pressure-volume constructs generated in dogs being weaned from cardiopulmonary bypass, recovers more quickly in animals pretreated with MLA. Cardiac protection in various models is associated with preservation of ATP during ischemia, induction of 5' nucleotidase and enhancement of calcium reuptake by SR during reperfusion. Limitation of infarct size by MLA in dogs and rabbits can be reversed by the administration of glibenclamide just prior to ischemia, suggesting a role for KATP channel opening during the first minutes of sustained ischemia. A clinical formulation of MLA (MPL-C) is currently undergoing clinical investigation in the Phase II setting in coronary artery bypass surgical patients. MLA may represent a novel means of inducing pharmacologic preconditioning, with potential for clinical application as a pretreatment before planned myocardial ischemia.
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PMID:Pharmacologic myocardial preconditioning with monophosphoryl lipid A (MLA) reduces infarct size and stunning in dogs and rabbits. 890 81

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

Tumour necrosis factor-alpha (TNF-alpha) is an autocrine contributor to myocardial dysfunction and cardiomyocyte death in ischaemia-reperfusion injury (I/R), sepsis, chronic heart failure and cardiac allograft rejection. Cardiac resident macrophages, infiltrating leucocytes, and cardiomyocytes themselves produce TNF-alpha. Although adenosine reduces macrophage TNF-alpha production and protects myocardium against I/R, it remains unknown whether I/R induces an increase in cardiac TNF-alpha in a crystalloid-perfused model (in the absence of blood), and, whether adenosine decreases cardiac TNF-alpha and protects function after I/R. To study this, isolated rat hearts were crystalloid-perfused using the Langendorff method and subjected to I/R, with or without adenosine pretreatment. Post-ischaemic cardiac TNF-alpha (enzyme-linked immunosorbent assay and bioassay) and function were determined (Langendorff). I/R increased cardiac TNF-alpha and impaired myocardial function. Adenosine decreased cardiac TNF-alpha and improved post-ischaemic functional recovery. This study demonstrates that: first, I/R induces an increase in cardiac tissue TNF-alpha in a crystalloid-perfused model: second, adenosine decreases cardiac TNF-alpha and improves post-ischaemic myocardial function; third, decreased cardiac TNF-alpha may represent a mechanism by which adenosine protects myocardium; and fourth, adenosine-induced suppression of cardiac TNF-alpha may provide an anti-inflammatory link to preconditioning and have implications for cardiac allograft preservation.
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PMID:Adenosine decreases post-ischaemic cardiac TNF-alpha production: anti-inflammatory implications for preconditioning and transplantation. 949 88

Sepsis depresses myocardial function but prevents subsequent ischemia-reperfusion injury. Elevated coronary flow (CF) and endogenous adenosine may be important factors in the complete recovery of postischemic myocardial function observed in septic rat hearts. The purpose of this study was to determine the effects of manipulating CF and of antagonizing adenosine receptors on the postischemic recovery of left ventricular developed pressure (LVDP) in septic and control rat hearts. The relationship between CF and LVDP in septic rat hearts before ischemia was depressed compared with control. However, this relationship was unaltered by ischemia in septic hearts, whereas in control hearts it was severely depressed. Preventing the elevation of CF during reperfusion did not significantly affect the recovery of LVDP in septic rat hearts. Adenosine antagonism by 8-phenyltheophylline (0.1 and 1 nM) prevented the elevated CF during reperfusion, and the higher dose significantly depressed postischemic function. We conclude that elevated CF did not contribute to the recovery of postischemic LVDP in septic rat hearts but that endogenous adenosine may provide protection from ischemia.
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PMID:The role of coronary flow and adenosine in postischemic recovery of septic rat hearts. 968 90

We report the history of a 60-year-old patient with a multiple myeloma and Staphylococcus aureus associated sepsis to whom adenosine in a dose of 6 mg was administered, when a regular, narrow QRS complex tachycardia at a heart rate of 120 beats/minute started. Adenosine led to a complete AV-block and revealed atrial flutter. Atrial flutter waves persisted for about 15 seconds and were followed by atrial and ventricular asystole for about 20 seconds. Repeated nonsustained polymorphic ventricular tachycardias followed and after about 90 seconds sinus rhythm was restored.
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PMID:Enlarged effects of adenosine in a septic patient with multiple myeloma and atrial flutter. 1294 44

The alpha 4/beta 1 integrin very late antigen-4 (CD49d/CD29) is up-regulated on circulating neutrophils of septic patients. Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression. TNF/fMLP stimulation also produced a similar increase in CD49d-mediated adhesion of neutrophils to a vascular cell adhesion molecule-1 (VCAM-1)-coated surface. Adenosine is a naturally occurring, anti-inflammatory mediator released from injured or inflamed tissues. We observed that stimulated neutrophil CD49d expression was decreased by activation of A(2A) adenosine receptors (A(2A)AR) with the selective agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylicacid methyl ester (ATL146e; EC(50)=6.4 nM). ATL146e (100 nM) also reduced the fraction of stimulated neutrophils that adhered to VCAM-1 from 38 +/- 6% to 27 +/- 5%. Inhibition of CD49d expression was equally inhibited by ATL146e, added before or after TNF priming, and was reversed by incubation with the A(2A)AR-selective antagonist 4-[2-[7-amino-2-(2-furyl) (1, 2, 4)triazolo(2,3-a) (1, 3, 5)triazin-5-yl-amino]ethyl]-phenol (ZM241385; 100 nM). A suboptimal ATL146e concentration (1 nM) combined with the type IV phosphodiesterase inhibitor rolipram (100 nM) synergistically decreased stimulated CD49d expression by >50%. The cyclic adenosine monophosphate (cAMP)-dependent kinase [protein kinase A (PKA)] inhibitor H-89 (10 microM) reversed the effect of ATL146e on stimulated CD49d expression. Other means of increasing cAMP in neutrophils also decreased stimulated CD49d expression. We conclude that adenosine binding to A(2A)AR counteracts stimulation of neutrophil CD49d integrin expression and neutrophil binding to VCAM-1 via a cAMP/PKA-mediated pathway.
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PMID:Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. 1452 68

Adenosine is a ubiquitous molecule that influences every physiological system studied thus far. In this review, we consider the influence of this purine nucleoside on some of the physiological systems affected during sepsis and SIRS. In the control of perfusion and cardiac output distribution, endogenous adenosine appears to play an important role in regulating perfusion in various vascular beds. Some of this control is mediated by stimulation of adenylyl cyclase, while part occurs by stimulating the production of nitric oxide. In the heart, adenosine may act as an inhibitory modulator of TNF-alpha expression. With regard to innate immune responses the effects of adenosine vary considerably, and are complex. However, the dominant responses relevant to SIRS indicate attenuation of inflammatory responses. Many of the effects of adenosine may also involve modulating oxyradical-mediated response. This occurs via increased oxyradical production via adenosine degradation (xanthine oxidase pathway), or limiting inflammatory oxyradical generation. Attempts to exploit the beneficial responses to adenosine have met with some success, and are considered here.
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PMID:Advances in understanding adenosine as a plurisystem modulator in sepsis and the systemic inflammatory response syndrome (SIRS). 1597 May 17

The mechanisms governing the impairment of bacterial clearance and immune function in sepsis are not known. Adenosine levels are elevated during tissue hypoxia and damage associated with sepsis. Adenosine has strong immunosuppressive effects, many of which are mediated by A(2A) receptors (A(2A)R) expressed on immune cells. We examined whether A(2A)R are involved in the regulation of immune function in cecal ligation and puncture-induced murine polymicrobial sepsis by genetically or pharmacologically inactivating A(2A)R. A(2A)R knockout (KO) mice were protected from the lethal effect of sepsis and had improved bacterial clearance compared with wild-type animals. cDNA microarray analysis and flow cytometry revealed increased MHC II expression in A(2A)-inactivated mice, suggesting improved Ag presentation as a mechanism of protection. Apoptosis was attenuated in the spleen of A(2A) KO mice indicating preserved lymphocyte function. Levels of the immunosuppressive cytokines IL-10 and IL-6 were markedly lower following A(2A)R blockade. Similar to observations with A(2A)R KO mice, an A(2A)R antagonist increased survival even when administered in a delayed fashion. These studies demonstrate that A(2A)R blockade may be useful in the treatment of infection and sepsis.
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PMID:Adenosine A2A receptor inactivation increases survival in polymicrobial sepsis. 1662 31


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