Protective effect of an adenosine kinase inhibitor in septic shock

Gs, Firestein; Boyle, D; Bullough, DA; He, Guanghua; Sajjadi, FG; Montag, Annika C.; Sambol, B; Mullane, K. M.

doi:10.1016/0300-9572(95)90695-e

Cited by 46 publications

(70 citation statements)

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“…[20][21][22][23] On the other hand, an excessive amount of TNF-a has also been implicated in the pathogenesis of many chronic inflammatory diseases. 24) Because of its pivotal role in pathogenesis, a significant effort has focused on developing therapeutic drugs that interfere with TNF-a production or action. 25,26) MC may be exerting its inhibitory effect on NO and TNFa production by simply being toxic to peritoneal macrophages.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

Chung

Kang

Cho

et al. 2007

Biological & Pharmaceutical Bulletin

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Moutan cortex, (MC) is one of the most widely used Oriental herbal medicines for treating inflammatory diseases. In this study, the effect of MC on lipopolysaccharide (LPS) and recombinant interferon‐gamma (rIFN‐γ)‐induced production of nitric oxide (NO) and tumor necrosis factor (TNF)‐alpha were examined using mouse peritoneal macrophages. MC inhibited the LPS/rIFN‐γ‐induced expression of inducible nitric oxide synthase (iNOS) and TNF‐alpha release. To clarify the mechanism involved, the effect of MC on the activation of nuclear factor (NF)‐kappaB was examined. The LPS/rIFN‐γ‐induced activation of NF‐kappaB was almost completely blocked by MC at 0.5 mg/ml. These findings demonstrate that the inhibition of the LPS/rIFN‐γ‐induced production of NO and TNF‐alpha by MC is due to the inhibition of NF‐kappaB activation.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

Chung

Kang

Cho

et al. 2007

Biological & Pharmaceutical Bulletin

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“…In animal models, potentiating adenosine effects (by either administration of adenosine receptor agonists or inhibiting reuptake mechanisms) have been shown to improve outcomes in sepsis (1,12,34,37). The A 2a AR is known to have anti-inflammatory effects and therefore has been an adenosine receptor subtype evaluated for its potential role in sepsis.…”

Section: Discussionmentioning

confidence: 99%

A₁adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

Gallos

Ruyle

Emala

et al. 2005

American Journal of Physiology-Renal Physiology

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A 1 adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis. Am J Physiol Renal Physiol 289: F369 -F376, 2005. First published March 22, 2005; doi:10.1152/ajprenal.00470.2004.-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 (A1AR) activation reduces inflammation and apoptosis after ischemia-reperfusion injury. Therefore, we questioned whether A 1AR-mediated reduction of inflammation and apoptosis could improve mortality and organ dysfunction in a murine model of sepsis. A 1AR knockout mice (A1 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 A1 wild-type mice treated with 1,3-dipropyl-8-cyclopentylxanthine (a selective A 1AR antagonist) had a significantly higher mortality rate compared with A 1 wild-type mice following CLP. Mice lacking endogenous A 1ARs demonstrated significant elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and tumor necrosis factor-␣ 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 A1AR activation confers a protective effect in mice from septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.acute renal failure; multiorgan injury; survival SEPSIS REPRESENTS A MAJOR clinical problem in hospitalized patients. Despite advances in antibiotic, hemodynamic, and ventilatory support, the incidence of sepsis and the numbers of sepsis-related deaths are increasing. On an annual basis, sepsis affects ϳ750,000 patients in the United States and accounts for nearly 215,000 deaths (2). Development of sepsis-induced organ injury and subsequent progression to acute organ dysfunction are associated with increased morbidity and mortality.Although the pathogenesis of sepsis-induced acute organ injury and dysfunction is not completely understood, the initial hyperinflammatory process and subsequent hypoimmune phase contribute to mortality and morbidity in sepsis. The initial hyperinflammatory response seen in sepsis is associated with uncontrolled, hyperexuberant cytokine production that can be deleterious to various tissues and leads to organ injury and dysfunction. After this hyperinflammatory phase, a hypoimmune phase ensues with enhanced apoptotic cell death occurring in multiple organs including the spleen, kidney, liver, and he...

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“…Recently, it has been reported that the use of specific adenosine kinase inhibitors in a murine and a rat sepsis model resulted in enhanced survival and moderately decreased TNF plasma levels [15].…”

Section: Discussionmentioning

confidence: 99%

Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis

et al. 1997

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Eigler A, Greten TF, Sinha B, Haslberger C, Sullivan GW, Endres S. Endogenous Adenosine Curtails Lipopolysacaride-Stimulated Tumour Necrosis Factor Synthesis. Scand J Immunol 1997;45:132-139 Recent studies have demonstrated the inhibitory effect of exogenous adenosine on TNF production. During inflammation endogenous adenosine levels are elevated and may be one of several anti-inflammatory mediators that reduce TNF synthesis. In the present study the authors investigated this role of adenosine in freshly isolated human PBMC. The effect of endogenous adenosine on TNF formation was studied by four different approaches. First, adenosine deaminase was added to LPS-stimulated mononuclear cells. This enzyme specifically deaminates extracellular adenosine to the inactive metabolite inosine. TNF production was augmented from baseline stimulation (LPS alone) of 3.5 ± 0.4 ng ml -1 -5.2 ± 0.9 ng ml -1 in the presence of 10 U ml -1 adenosine deaminase. Second, TNF production was determined after stimulation in the presence of dipyridamole, an inhibitor of cellular re-uptake of adenosine which increases extracellular concentrations. TNF synthesis was reduced dose-dependently from 3.1 ± 0.9 ng ml -1 -1.1 ± 0.2 ng ml -1 by 10 M dipyridamole. Third, the adenosine A 2 receptor antagonist 8-(3-chlorostyryl)caffeine (100 nM) enhanced TNF synthesis from a baseline of 3.7 ± 0.5 ng ml -1 -5.5 ± 0.9 ng ml -1 . In contrast, no increase resulted from the addition of 100 nM of the specific A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Finally, the authors were able to show that suppression of TNF formation by the specific type IV phosphodiesterase inhibitor rolipram can be completely reversed by adenosine deaminase or by the application of the A 2 receptor antagonist. The authors conclude that endogenous adenosine controls TNF production. This effect of adenosine may not only have a physiological role but also appears to contribute to the pharmacological inhibition of TNF synthesis by exogenous agents such as the specific type IV phosphodiesterase inhibitor rolipram.

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Protective effect of an adenosine kinase inhibitor in septic shock

Cited by 46 publications

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Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

A₁adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis

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Protective effect of an adenosine kinase inhibitor in septic shock

Cited by 46 publications

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Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

Inhibition of Nitric Oxide and Tumor Necrosis Factor-Alpha by Moutan Cortex in Activated Mouse Peritoneal Macrophages

A1adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis

Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis

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A₁adenosine receptor knockout mice exhibit increased mortality, renal dysfunction, and hepatic injury in murine septic peritonitis