Effect of a specific and selective A2B adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma
Effect of a specific and selective A2B adenosine receptor antagonist on adenosine agonist AMP and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma
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DOI：
10.1124/jpet.106.112250
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Zeng, Dewan
中科院分区：
文献类型：
--
作者：
Mustafa, S. Jamal;Nadeem, Ahmed;Zeng, Dewan
以前已经提出腺苷在哮喘的发病机制中起重要作用。提出的核苷腺苷的作用机制是激活A（2B）腺苷受体（AR）并间接调节肺中介质的水平。缺乏支持A（2B）AR在过敏性动物模型中气道反应性和炎症中作用的体内数据。本研究描述了选择性A（2B）AR拮抗剂CVT-6883 [3-乙基-1-丙基-8-[1-（3-三氟甲基苄基）-1H-吡唑-4-基]-3，7-二氢嘌呤-2，6-二酮]对过敏性哮喘小鼠模型气道反应性和炎症的影响。将小鼠用豚草（i. p.）在第1天和第6天用0.5%豚草攻击，并在第11、12和13天用0.5%豚草攻击。在第14天，根据增强的暂停（Penh）测量对5 '-N-乙基羧酰胺腺苷（NECA）、AMP或过敏原激发的气道反应性。雾化NECA引起Penh浓度依赖性增加，CVT-6883（0.4、1.0或2.5 mg/kg i. p.）显著减弱了这种增加。雾化AMP在致敏小鼠中引起Penh的显著增加，并且通过CVT-6883（lmg/kg i. p.）或孟鲁司特（1 mg/kg i. p.）。过敏原激发在致敏小鼠中诱导迟发性过敏反应，其被CVT-6883（1 mg/kg i. p.）抑制。过敏原攻击也增加了从致敏小鼠获得的支气管肺泡灌洗液中的细胞数量，并且通过CVT-6883（6 mg/ml雾化5分钟）或茶碱（36 mg/ml雾化5分钟）减少。这些结果表明，A（2B）AR拮抗剂在抑制过敏性哮喘模型的气道反应性和炎症中起重要作用。
It has been previously proposed that adenosine plays an important role in the pathogenesis of asthma. The proposed mechanism of action for nucleoside adenosine is to activate A(2B) adenosine receptors (AR) and to indirectly modulate levels of mediators in the lung. In vivo data supporting the role of A(2B)AR in airway reactivity and inflammation in allergic animal models are lacking. The present study describes the effects of a selective A(2B)AR antagonist, CVT-6883 [3-ethyl-1-propyl-8-[1-(3-trifluoromethylbenzyl)-1H-pyrazol-4-yl]-3,7-dihydropurine-2,6-dione], on airway reactivity and inflammation in an allergic mouse model of asthma. Mice were sensitized with ragweed (i.p.)on days 1 and 6 and challenged with 0.5% ragweed on days 11, 12, and 13. On day 14, airway reactivity to 5'-N-ethylcarboxamidoadenosine ( NECA), AMP, or allergen challenge was measured in terms of enhanced pause ( Penh). Aerosolized NECA elicited concentration-dependent increases in Penh, which were significantly attenuated by CVT-6883 (0.4, 1.0, or 2.5 mg/kg i.p.). Aerosolized AMP elicited significant increases in Penh in sensitized mice, and the effect was significantly attenuated by either CVT-6883 ( 1 mg/kg i.p.) or montelukast ( 1 mg/kg i.p.). Allergen challenge induced late allergic response in sensitized mice, which was inhibited by CVT-6883 ( 1 mg/kg i.p.). Allergen challenge also increased the number of cells in bronchoalveolar lavage fluid obtained from sensitized mice, and that was reduced by either CVT-6883 ( 6 mg/ml aerosolization for 5 min) or theophylline ( 36 mg/ml aerosolization for 5 min). These results suggest that A(2B)AR antagonism plays an important role in inhibition of airway reactivity and inflammation in this model of allergic asthma.