Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

Mantell, Simon J.; Stephenson, Peter T.; Monaghan, Sandra M.; Maw, Graham N.; Trevethick, Michael A.; Yeadon, Michael; Keir, Ruth F.; Walker, Don K.; Jones, Rhys; Selby, Matthew D.; Batchelor, David V.; Rozze, Stuart; Chavaroche, Helene; Hobson, Tim J.; Dodd, Peter G.; Lemaitre, Arnaud; Wright, Kate; Stuart, Emilio F.

doi:10.1016/j.bmcl.2008.01.033

Cited by 23 publications

(17 citation statements)

References 16 publications

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“…We believe this noticeable increase in intracellular adenosine resulted as a consequence of the hypoxic environment and the rapid hydrolysis of ATP induced by smoke extract exposure (44)(45)(46). Of the four receptors, the adenosine A 2A receptor is strongly linked to controlling inflammation and tissue protection (47,48). Our data demonstrate that cigarette smoke exposure not only increases the mRNA expression of A 2A AR, but also that of the other adenosine receptors.…”

Section: Discussionmentioning

confidence: 48%

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Allen‐Gipson

Zimmerman²,

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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Adenosine concentrations are elevated in the lungs of patients with asthma and chronic obstructive pulmonary disease, where it balances between tissue repair and excessive airway remodeling. We previously demonstrated that the activation of the adenosine A 2A receptor promotes epithelial wound closure. However, the mechanism by which adenosine-mediated wound healing occurs after cigarette smoke exposure has not been investigated. The present study investigates whether cigarette smoke exposure alters adenosine-mediated reparative properties via its ability to induce a shift in the oxidant/ antioxidant balance. Using an in vitro wounding model, bronchial epithelial cells were exposed to 5% cigarette smoke extract, were wounded, and were then stimulated with either 10 mM adenosine or the specific A 2A receptor agonist, 59-(N-cyclopropyl)-carboxamidoadenosine (CPCA; 10 mM), and assessed for wound closure. In a subset of experiments, bronchial epithelial cells were infected with adenovirus vectors encoding human superoxide dismutase and/or catalase or control vector. In the presence of 5% smoke extract, significant delay was evident in both adenosine-mediated and CPCA-mediated wound closure. However, cells pretreated with N-acetylcysteine (NAC), a nonspecific antioxidant, reversed smoke extract-mediated inhibition. We found that cells overexpressing mitochondrial catalase repealed the smoke extract inhibition of CPCA-stimulated wound closure, whereas superoxide dismutase overexpression exerted no effect. Kinase experiments revealed that smoke extract significantly reduced the A 2A -mediated activation of cyclic adenosine monophosphate-dependent protein kinase. However, pretreatment with NAC reversed this effect. In conclusion, our data suggest that cigarette smoke exposure impairs A 2A -stimulated wound repair via a reactive oxygen species-dependent mechanism, thereby providing a better understanding of adenosine signaling that may direct the development of pharmacological tools for the treatment of chronic inflammatory lung disorders.

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Section: Discussionmentioning

confidence: 48%

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Allen‐Gipson

Zimmerman²,

Zhang³

et al. 2013

Am J Respir Cell Mol Biol

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“…However, adenosine insertions at certain positions of single‐stranded DNA can result in loss of the inhibitory effect. Adenosines can be anti‐inflammatory through the A(2A) receptor 71–74 . Synergistic interaction has been reported 75,76 between the A(2A) receptor and the receptors TLR2, TLR3, TLR4, TLR7 and TLR9, resulting in down‐regulation of tumour necrosis factor‐α release upon murine macrophage activation and human peripheral blood mononuclear cell stimulation.…”

Section: Discussionmentioning

confidence: 99%

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

et al. 2012

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SummaryThe Toll-like receptors (TLRs) 3, 7, 8 and 9 stimulate innate immune responses upon recognizing pathogen-derived nucleic acids. TLR3 is located on the cell surface and in cellular endosomes and recognizes double-stranded viral RNA or the synthetic mimic poly rI:rC. Recently, unformulated small interfering RNA (siRNA) has been reported as ligand for surface-expressed murine TLR3. Blockage of TLR3 is achieved by singlestranded DNA. We confirm and expand the observation that poly rI:rCmediated TLR3 immune activation is blocked in a sequence-, length-, backbone-and CpG-dependent manner. However, human TLR3 is not activated by siRNA, which may be the result of differences in the amino acid composition of the TLR3 loop 1 of mice and humans. Although CD14 was previously described as a co-receptor for murine TLR3 and other nucleic acid-recognizing TLRs, human CD14 acts only as co-receptor to human TLR9, but not TLR3, TLR7 or TLR8. We show that CD14 up-regulates the TLR9 immune response of A, B and C-class oligodeoxynucleotides but down-regulates the phosphoro-diester version of B-class oligodeoxynucleotides.

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“…UK371,104 is a potent and selective agonist of the human adenosine A 2A receptor ( Barnard et al ., 2007 ; Mantell et al ., 2008 ), which also inhibits mediator release from human isolated neutrophils (Table 1). In this regard, the overall in vitro anti‐inflammatory profile of UK371,104 is very similar to CGS21680 (Table 1).…”

Section: Uk371104: An Inhaled Adenosine A2a Receptor Agonist With a mentioning

confidence: 99%

Treating lung inflammation with agonists of the adenosine A_2A receptor: promises, problems and potential solutions

Trevethick

Mantell

Stuart

et al. 2008

British J Pharmacology

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Adenosine A 2A receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A 2A agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A 2A antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation in a wide variety of in vivo models. Inflammation is a hallmark of asthma and COPD and adenosine has long been suggested to be involved in disease pathology. Two recent publications, however, suggested that an inhaled adenosine A 2A receptor agonist (GW328267X) did not affect either the early and late asthmatic response or symptoms associated with allergic rhinitis suggesting that the rationale for treating inflammation with an adenosine A 2A receptor agonist may be incorrect. A barrier to fully investigating the role of adenosine A 2A receptor agonists as anti-inflammatory agents in the lung is the side effect profile due to systemic exposure, even with inhalation. Unless strategies can be evolved to limit the systemic exposure of inhaled adenosine A 2A receptor agonists, the promise of treating lung inflammation with such agents may never be fully explored. Using strategies similar to that devised to improve the therapeutic index of inhaled corticosteroids, UK371,104 was identified as a selective agonist of the adenosine A 2A receptor that has a lung focus of pharmacological activity following delivery to the lung in a pre clinical in vivo model of lung function. Lung-focussed agents such as UK371,104 may be suitable for assessing the anti-inflammatory potential of inhaled adenosine A 2A receptor agonists.

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Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

Cited by 23 publications

References 16 publications

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

Treating lung inflammation with agonists of the adenosine A_2A receptor: promises, problems and potential solutions

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Inhaled adenosine A2A receptor agonists for the treatment of chronic obstructive pulmonary disease

Cited by 23 publications

References 16 publications

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Smoke Extract Impairs Adenosine Wound Healing. Implications of Smoke-Generated Reactive Oxygen Species

Toll‐like receptor (TLR) 3 immune modulation by unformulated small interfering RNA or DNA and the role of CD14 (in TLR‐mediated effects)

Treating lung inflammation with agonists of the adenosine A2A receptor: promises, problems and potential solutions

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Product

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Treating lung inflammation with agonists of the adenosine A_2A receptor: promises, problems and potential solutions