Adenosine Receptor Ligands: Potential as Therapeutic Agents in Asthma and COPD

Fozard, John R.; Hannon, Jason P.

doi:10.1006/pupt.1999.0191

Cited by 94 publications

(97 citation statements)

References 3 publications

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“…Similarly, the present study shows that the A1AR is downregulated on microglia during MOG-EAE. These findings suggest that transcriptional control or transcript degradation of A1AR gene was perturbed during CNS inflammation, which is in contrast with findings in asthma, in which antagonism of the A1AR improves outcomes (Fozard and McCarthy, 2002). The expression ϩ/ϩ and A1AR Ϫ/Ϫ animals with oligodendrocyte cytotoxicity.…”

Section: Discussionmentioning

confidence: 78%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

298

265

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The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR Ϫ/Ϫ ) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR ϩ/ϩ ) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR Ϫ/Ϫ animals. In addition, spinal cords from A1AR Ϫ/Ϫ mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR ϩ/ϩ animals. Macrophages from A1AR Ϫ/Ϫ animals exhibited increased expression of the proinflammatory genes, interleukin-1␤, and matrix metalloproteinase-12 on immune activation when matched with A1AR ϩ/ϩ control cells. A1AR Ϫ/Ϫ macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR ϩ/ϩ mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.

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Section: Discussionmentioning

confidence: 78%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

298

265

View full text Add to dashboard Cite

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“…5). Because enprofylline is a relatively selective A 2B antagonist with K i values of 7 and 65 M for A 2B and A 3 receptors, respectively (10), it was still difficult to make conclusions about the role of A 2B receptors from this experiment. Further supporting data were obtained using a combination of enprofylline with MRS1523, which showed that the partial inhibition of NECA-induced bronchoconstriction was completely blocked by a combination of enprofylline and MRS1523.…”

Section: Discussionmentioning

confidence: 93%

Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model

Fan

Qin

Mustafa

2003

American Journal of Physiology-Lung Cellular and Molecular Phys

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Fan, Ming, Weixi Qin, and S. Jamal Mustafa. Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model. Am J Physiol Lung Cell Mol Physiol 284: L1012-L1019, 2003. First published January 17, 2003 10.1152/ajplung.00353.2002We recently reported that adenosine caused bronchoconstriction and enhanced airway inflammation in an allergic mouse model. In this study, we further report the characterization of the subtype of adenosine receptor(s) involved in bronchoconstriction. 5Ј-(N-ethylcarboxamido)adenosine (NECA), a nonselective adenosine agonist, elicited bronchoconstriction in a dose-dependent manner. Little effects of N 6 -cyclopentyladenosine (A1-selective agonist) and 2-p-(2-carboxyethyl)phenethylamino-5Ј-Nethylcarboxamidoadenosine (A2A-selective agonist) compared with NECA were observed in this model. 2-Chloro-N 6 -(3-iodobenzyl)-9-[5-(methylcarbamoyl)-␤-D-ribofuranosyl]adenosine, an A3-selective receptor agonist, produced a dose-dependent bronchoconstrictor response, which was blocked by selective A3 antagonist 2,3-diethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523). However, MRS1523 only partially inhibited NECA-induced bronchoconstriction. Neither selective A1 nor A2A antagonists affected NECA-induced bronchoconstriction. Enprofylline, a relatively selective A2B receptor antagonist, blocked partly NECA-induced bronchoconstriction. Furthermore, a combination of enprofylline and MRS1523 completely abolished NECA-induced bronchoconstrictor response. Using RT-PCR, we found that all four adenosine receptor subtypes are expressed in control lungs. Allergen sensitization and challenge significantly increased transcript levels of the A2B and A3 receptors, whereas the A1 receptor message decreased. No change in transcript levels of A2A receptors was observed after allergen sensitization and challenge. These findings suggest that A2B and A3 adenosine receptors play an important role in adenosine-induced bronchoconstriction in our allergic mouse model. Finally, whether the airway effects of the receptor agonists/antagonists are direct or indirect needs further investigations. adenosine agonists; adenosine antagonists; mouse lung; asthma AMONG THE MANY ACTIONS of adenosine, several lines of evidence suggest a contribution of adenosine to the pathophysiology of asthma. Adenosine is present in high concentrations in the bronchoalveolar lavage fluid of asthmatics (8). Airway preparations from allergic asthmatic subjects are more sensitive to the contractile responses of adenosine and related analogs (4). Inhaled adenosine causes bronchoconstriction in asthmatics and allergic nonasthmatics compared with normal subjects (24).The response of the asthmatic airways to adenosine involves the activation of extracellular adenosine receptor(s). Theophylline, a nonselective adenosine receptor antagonist, selectively (relative to histamine) inhibited adenosine-induced bronchoconstriction at doses generating plasma concentrations that are insuffic...

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“…A good example for this notion is our recent observation that A 2A receptor blockade can promote antibacterial immunity and bacterial clearance in septic animals (Nemeth et al, 2006). Finally, there is convincing evidence that selective adenosine receptor antagonists (A 2B and A 3 ) are potential therapeutics for asthma and chronic lung disease (Fozard & Hannon, 1999;Fozard & McCarthy, 2002;Blackburn, 2003;Fozard, 2003;Mohsenin & Blackburn, 2006;Spicuzza et al, 2006). Hopefully, the success of adenosinergic ligands as therapeutic interventions in experimental disease models will be replicated in human ailments in the not so distant future.…”

Section: Therapeutic Implicationsmentioning

confidence: 98%

“…In general, A 1 and A 3 receptors are coupled to pertussis toxin-inhibited G i coupled signal transduction proteins or directly to ion channels whereas A 2 receptors (A 2A and A 2B ) are Gα S -linked receptors and stimulate adenylyl cyclase and camp accumulation. Adenosine receptors or receptor-mediated effects have been demonstrated in virtually every tissue or organ examined Ralevic & Burnstock, 1998;Fozard & Hannon, 1999;Fredholm et al, 2001;Linden, 2001;Fozard & McCarthy, 2002;Hasko et al, 2002;Hasko & Cronstein, 2004;Fredholm et al, 2005).…”

Section: Adenosine Receptorsmentioning

confidence: 99%

Shaping of monocyte and macrophage function by adenosine receptors

Haskó

Pacher

Deitch

et al. 2007

Pharmacology & Therapeutics

194

154

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Adenosine is an endogenous purine nucleoside that, following its release into the extracellular space, binds to specific adenosine receptors expressed on the cell surface. Adenosine appears in the extracellular space under metabolically stressful conditions, which are associated with ischemia, inflammation, and cell damage. There are 4 types of adenosine receptors (A 1 , A 2A , A 2B and A 3 ) and all adenosine receptors are members of the G protein-coupled family of receptors. Adenosine receptors are expressed on monocytes and macrophages and through these receptors adenosine modulates monocyte and macrophage function. Since monocytes and macrophages are activated by the same danger signals that cause accumulation of extracellular adenosine, adenosine receptors expressed on macrophages represent a sensor system that provide monocytes and macrophages with information about the stressful environment. Adenosine receptors, thus, allow monocytes and macrophages to fine-tune their responses to stressful stimuli. Here, we review the consequences of adenosine receptor activation on monocyte/macrophage function. We will detail the effect of stimulating the various adenosine receptor subtypes on macrophage differentiation/proliferation, phagocytosis, and tissue factor (TF) expression. We will also summarize our knowledge of how adenosine impacts the production of extracellular mediators secreted by monocytes and macrophages in response to toll-like receptor (TLR) ligands and other inflammatory stimuli. Specifically, we will delineate how adenosine affects the production of superoxide, nitric oxide (NO), tumor necrosis factor-α, interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). A deeper insight into the regulation of monocyte and macrophage function by adenosine receptors should assist in developing new therapies for inflammatory diseases.

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Adenosine Receptor Ligands: Potential as Therapeutic Agents in Asthma and COPD

Cited by 94 publications

References 3 publications

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Characterization of adenosine receptor(s) involved in adenosine-induced bronchoconstriction in an allergic mouse model

Shaping of monocyte and macrophage function by adenosine receptors

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