Animal models of asthma have shown that limonene, a naturally occurring terpene in citrus fruits, can reduce inflammation and airway reactivity. However, the mechanism of these effects is unknown. We first performed computational and molecular docking analyses that showed limonene could bind to both A_2A and A_2B receptors. The pharmacological studies were carried out with A_2A adenosine receptor knock-out (A_2AKO) and wild-type (WT) mice using ovalbumin (OVA) to generate the asthma phenotype. We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) and NECA (nonselective adenosine analog) by administering limonene as an inhalation prior to OVA aerosol challenges in one group of allergic mice for both WT and KO. In whole-body plethysmography studies, we observed that airway responsiveness to MCh in WT SEN group was significantly lowered upon limonene treatment but no effect was observed in A_2AKO. Limonene also attenuated NECA-induced airway responsiveness in WT allergic mice with no effect being observed in A_2AKO groups. Differential BAL analysis showed that limonene reduced levels of eosinophils in allergic WT mice but not in A_2AKO. However, limonene reduced neutrophils in sensitized A_2AKO mice, suggesting that it may activate A_2B receptors as well. These data indicate that limonene-induced reduction in airway inflammation and airway reactivity occurs mainly via activation of A_2AAR but A_2B receptors may also play a supporting role.

哮喘动物模型表明，柠檬烯是柑橘类水果中天然存在的萜烯，可以减少炎症和气道反应性。然而，这些影响的机制尚不清楚。我们首先进行了计算和分子对接分析，结果表明柠檬烯可以与 A _2A和 A _2B受体结合。用A _2A腺苷受体敲除（A _2AKO) 和野生型 (WT) 小鼠使用卵清蛋白 (OVA) 产生哮喘表型。我们在一组 WT 和 KO 的过敏小鼠中，通过在 OVA 气雾剂挑战之前吸入柠檬烯，研究了柠檬烯对肺部炎症和气道对乙酰甲胆碱 (MCh) 和 NECA（非选择性腺苷类似物）反应的影响。在全身体积描记研究中，我们观察到 WT SEN 组对 MCh 的气道反应性在柠檬烯治疗后显着降低，但在 A _2A KO 中未观察到影响。在 WT 过敏小鼠中，柠檬烯还减弱了 NECA 诱导的气道反应性，而在 A _2A KO 组中没有观察到任何影响。差异 BAL 分析表明，柠檬烯降低了过敏 WT 小鼠的嗜酸性粒细胞水平，但在 A_2A KO。然而，柠檬烯减少了致敏 A _2A KO 小鼠的中性粒细胞，表明它也可能激活 A _2B受体。这些数据表明，柠檬烯诱导的气道炎症和气道反应性降低主要通过激活 A _2A AR 而发生，但 A _2B受体也可能起到支持作用。