Activation of Adenosine A<sub>2a</sub> Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction

Fenster, Michael S.; Shepherd, Rebecca K.; Linden, Joel; Duling, B. R.

doi:10.1038/sj.mn.7300101

Cited by 12 publications

(15 citation statements)

References 24 publications

(34 reference statements)

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“…In addition, Rork et al (2008) found that activation of A 2A receptors can limit mast cell degranulation in the murine heart, decreasing reperfusion injury. A study using cheek pouch of the golden hamster also revealed an inhibitory effect of activation of A 2A receptors on inosine-induced periarteriolar mast cell degranulation (Fenster et al, 2000). In contrast, our mouse studies both in vitro and in vivo do not support a role for A 2A receptors in antigen-induced mast cell degranulation.…”

Section: Discussioncontrasting

confidence: 52%

“…It is possible that the environment in which the mast cell resides influences adenosine receptor expression and function, accounting for the differences in receptor effects observed between these studies. Although several studies have suggested that A 2A receptors mediate anti-inflammatory effects (Antonioli et al, 2010;Fenster et al, 2000;Harada et al, 2000;Kreckler et al, 2006;Rork et al, 2008;Trevethick et al, 2008), a clinical trial failed to demonstrate efficacy of an A 2A agonist in attenuating allergen-induced early and late reactions, sputum total cell counts and EG21 cell numbers, eosinophil cationic protein levels, or inflammatory cytokine production in asthmatic subjects (Luijk et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Hua

Chason

Jania

et al. 2012

J Pharmacol Exp Ther

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Mast cell activation results in the immediate release of proinflammatory mediators prestored in cytoplasmic granules, as well as initiation of lipid mediator production and cytokine synthesis by these resident tissue leukocytes. Allergen-induced mast cell activation is central to the pathogenesis of asthma and other allergic diseases. Presently, most pharmacological agents for the treatment of allergic disease target receptors for inflammatory mediators. Many of these mediators, such as histamine, are released by mast cells. Targeting pathways that limit antigen-induced mast cell activation may have greater therapeutic efficacy by inhibiting the synthesis and release of many proinflammatory mediators produced in the mast cell. In vitro studies using cultured human and mouse mast cells, and studies of mice lacking A 2B receptors, suggest that adenosine receptors, specifically the G s -coupled A 2A and A 2B receptors, might provide such a target. Here, using a panel of mice lacking various combinations of adenosine receptors, and mast cells derived from these animals, we show that adenosine receptor agonists provide an effective means of inhibition of mast cell degranulation and induction of cytokine production both in vitro and in vivo. We identify A 2B as the primary receptor limiting mast cell degranulation, whereas the combined activity of A 2A and A 2B is required for the inhibition of cytokine synthesis.

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Section: Discussioncontrasting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Hua

Chason

Jania

et al. 2012

J Pharmacol Exp Ther

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“…Note that in the severe stunning group (group 2), there was significantly greater recovery as early as 5 min in the AA2A agonist-treated subgroup vs. control. plasma membranes, and stimulation of these receptors inhibits these cells from degranulating (17).…”

Section: Discussionmentioning

confidence: 99%

Cardioprotection by adenosine A_2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia

Glover¹,

Ruiz²,

Petruzella³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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GA. Cardioprotection by adenosine A2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Am J Physiol Heart Circ Physiol 292: H3164 -H3171, 2007. First published February 16, 2007; doi:10.1152/ajpheart.00743.2005.-We sought to determine whether administration of a very low, nonvasodilating dose of a highly selective adenosine A2A receptor agonist or ATL-146e) would be cardioprotective in a canine model of myocardial stunning produced by multiple episodes of transient ischemia. Twenty-four anesthetized open-chest dogs underwent either 4 (n ϭ 12) or 10 cycles (n ϭ 12) of 5-min left anterior descending coronary artery (LAD) occlusions interspersed by 5 or 10 min of reperfusion. Left ventricular thickening was measured from baseline through 180 min after the last occlusion-reperfusion cycle. Regional flow was measured with microspheres. In 12 of 24 dogs, A2A receptor agonist was infused intravenously beginning 2 min prior to the first occlusion and continuing throughout reperfusion at a dose below that which produces vasodilatation (0.01 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Myocardial flow was similar between control and A2A receptor agonist-treated animals, confirming the absence of A2 receptor agonist-induced vasodilatation. During occlusion, there was severe dyskinesis with marked LAD zone thinning in all animals. After 180 min of reperfusion following the last cycle, significantly greater recovery of LAD zone thickening was observed in A2A receptor agonist-treated vs. control animals in both the 4-cycle (91 Ϯ 7 vs. 56 Ϯ 12%, respectively; P Ͻ 0.05) and the 10-cycle (65 Ϯ 9 vs. 8 Ϯ 16%, respectively; P Ͻ 0.05) occlusion groups. The striking amount of functional recovery observed with administration of low, nonvasodilating doses of adenosine A2A agonist ATL-193 or ATL-146e supports their further evaluation for the attenuation of postischemic stunning in the clinical setting. left ventricular dysfunction; demand ischemia; reperfusion injury MYOCARDIAL STUNNING IS A FORM of reversible reperfusion injury characterized by prolonged depression of left ventricular (LV) contractile function in viable myocardium despite restoration of normal or near-normal resting blood flow (7,28). Clinical studies have demonstrated that many patients with coronary artery disease experience repetitive episodes of myocardial ischemia in the same vascular territory while going about their daily activities (14). Echocardiographic and radionuclide studies have demonstrated that severe postischemic contractile dysfunction, or myocardial stunning, occurs following periods of exercise or pharmacological stress-induced ischemia (15,30,34). Importantly, animal studies have shown that frequent episodes of myocardial ischemia that occur in close temporal proximity have a cumulative effect on the deterioration of myocardial contractility, and some (29, 33, 52) have proposed that repetitive myocardial stunning following demand ischemia is the mechanism for myocardial hibernation. In addition, this phenomenon has ...

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“…Some candidate targets of A 2A agonists are mast cells (19), platelets (20), macrophages (21), dendritic cells (22), and T lymphocytes (23). Macrophages and dendritic cells are APCs and serve to initiate inflammation in response to invading microorganisms.…”

Section: Discussionmentioning

confidence: 99%

A2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury

Day

Rieger

et al. 2005

The Journal of Immunology

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Activation of the A2A adenosine receptor (A2AR) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A2AR on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester (ATL313; 3 μg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-γ-inducible protein-10, IL-1α, IL-1-β, IL-1Rα, IL-18, IL-6, and IFN-γ), or histological criteria. ATL313, which is highly selective for the A2AR, produces more liver protection of chimeric BMT mice than 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid, which has similar affinity for the A2AR and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A2AR on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.

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Activation of Adenosine A_2a Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction

Abstract: We conclude that mast cell degranulation can be inhibited via activation of an adenosine A2 alpha receptor; which activation occurs at a lower concentration of adenosine than stimulatory A3 receptor activation. This finding may have implications for the pathology of ischemia.

Cited by 12 publications

References 24 publications

G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Cardioprotection by adenosine A_2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia

A2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury

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Activation of Adenosine A2a Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction

Abstract: We conclude that mast cell degranulation can be inhibited via activation of an adenosine A2 alpha receptor; which activation occurs at a lower concentration of adenosine than stimulatory A3 receptor activation. This finding may have implications for the pathology of ischemia.

Cited by 12 publications

References 24 publications

Gs-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Gs-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Cardioprotection by adenosine A2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia

A2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury

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Resources

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Activation of Adenosine A_2a Receptors Inhibits Mast Cell Degranulation and Mast Cell‐Dependent Vasoconstriction

G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

G_s-Coupled Adenosine Receptors Differentially Limit Antigen-Induced Mast Cell Activation

Cardioprotection by adenosine A_2A agonists in a canine model of myocardial stunning produced by multiple episodes of transient ischemia