Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells.

Cronstein, Bruce N.; Levin, Richard I.; Belanoff, Joseph K.; Weissmann, Gerald; Hirschhorn, Rochelle

doi:10.1172/jci112638

Cited by 399 publications

(175 citation statements)

References 36 publications

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“…In addition to the previously reported inhibitory effects of adenosine on the synthesis of pro-inflammatory cytokines, such as TNF-a (Le Vraux et al, 1993;Parmely et al, 1993;Bouma et al, 1994) and IL-8 (Bouma et al, 1994), the adherence of PMN to endothelial cells (Cronstein et al, 1986), and the generation of superoxide anions (Cronstein et al, 1990), the ability of adenosine and adenosine-elevating agents to inhibit the synthesis of LTB4 (in the current study) provides additional impetus towards the use of selective A2 receptor agonists (or agents that affect the in vivo metabolism of adenosine) in the treatment of sepsis, a complex inflammatory condition which may only be controlable by a multi-target therapeutic approach.…”

Section: Discussionmentioning

confidence: 80%

Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo

Krump

Lemay

Borgeat

1996

British J Pharmacology

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Engagement of adenosine A2 receptors suppresses several leukocyte functions. In the present study, we examined the effect of adenosine on the inhibition of leukotriene B4 (LTB4) synthesis in heparinized human whole blood, pretreated with lipopolysaccharide (LPS) and tumour necrosis factor α (TNF‐α) and stimulated with the chemotactic peptide, N‐formyl‐Met‐Leu‐Phe (FMLP). The FMLP‐induced synthesis of LTB4 in whole blood pretreated with LPS and TNF‐α was dose‐dependently inhibited by adenosine analogues in the following order of potency; 5′(N‐ethyl)carbox‐ amidoadenosine (NECA) ≅ CGS 21680 > 2‐Cl‐adenosine > N6‐cyclopentyladenosine (CPA), indicating the involvement of the adenosine A2 receptor subtype. The IC50 values for NECA, CGS 21680, 2‐Cl‐ adenosine, and CPA were 6nM, 9nM, 180nM, and 990 nM, respectively. Dipyridamole, an agent that blocks the cellular uptake of adenosine by red cells and causes its accumulation in plasma, also inhibited the synthesis of LTB4 in LPS and TNF‐α‐treated whole blood stimulated by FMLP; moreover, this inhibition was reversed upon addition of adenosine deaminase. A highly selective antagonist of the adenosine A2 receptor, 8‐(3‐chlorostyryl)caffeine (CSC), reversed the inhibition of LTB4 synthesis by 2‐Cl‐adenosine and dipyridamole in LPS and TNF‐α‐treated whole blood, stimulated by FMLP. LTB4 synthesis in whole blood originates predominantly from neutrophils and to a lesser extent from monocytes. 2‐Cl‐adenosine also inhibited the synthesis of LTB4 induced by FMLP in these isolated LPS and TNF‐α‐treated cells; however, 2‐Cl‐adenosine was a more potent inhibitor of LTB4 synthesis in neutrophils than monocytes. The present data demonstrate that adenosine, acting through A2 receptors, exerts a potent inhibitory effect on the synthesis of LTB4 and thus contribute to the understanding of its anti‐inflammatory properties.

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Section: Discussionmentioning

confidence: 80%

Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo

Krump

Lemay

Borgeat

1996

British J Pharmacology

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“…Adenosine has been shown to inhibit neutrophil oxidative metabolism and adhesion to endothelial cells, to increase membrane stability and energy production by promoting glucose transport, and to reduce Ca 2ϩ influx through the activation of ATP-dependent K ϩ channels [72][73][74][75]. However, the role of all biochemical effects in adenosine-afforded protection is yet to be defined.…”

Section: Protective Mechanisms Of Early Ischemic Preconditioningmentioning

confidence: 99%

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Cutrn

Perrelli

Cavalieri

et al. 2002

Free Radical Biology and Medicine

150

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Abstract-Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-␣, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.

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“…This raises the question of what effect endogenously formed adenosine exerts on TNF synthesis. While the anti-inflammatory capacities of endogenously produced adenosine on neutrophil functions such as activation and adherence have been thoroughly investigated [17][18][19] this is not the case for its role in the control of TNF synthesis.…”

Section: Introductionmentioning

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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Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells.

Cited by 399 publications

References 36 publications

Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo

Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis

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Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells.

Cited by 399 publications

References 36 publications

Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

Adenosine A2 receptor‐induced inhibition of leukotriene B4 synthesis in whole blood ex vivo

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Endogenous Adenosine Curtails Lipopolysaccharide‐Stimulated Tumour Necrosis Factor Synthesis

Contact Info

Product

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Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo

Adenosine A₂ receptor‐induced inhibition of leukotriene B₄ synthesis in whole blood ex vivo