Limonene‐induced Activation of A2A Adenosine Receptors Reduces Airway Inflammation and Reactivity in a Mouse Model of Asthma

Abstract

Animal models of asthma have shown that limonene (terpene in citrus fruits) reduces inflammation and airway reactivity. However, the mechanism of these effects is unknown. We hypothesized that limonene activates A2A adenosine receptors (A2AAR) to produce its effects in asthma, after comparing Glide scores for limonene (−5.19) and A2AAR agonist CGS 21680 (−8.43). We investigated the effects of limonene on lung inflammation and airway responsiveness to methacholine (MCh) as well NECA (nonselective adenosine analog) in A2AAR knock‐out (A2AKO) and wild‐type (WT) mice. Mice were divided into control (CON) and allergen sensitized‐challenged (SEN) groups, and were sensitized i.p. on days 1, 6 with 20 μg ovalbumin (OVA) followed by 5% OVA aerosol challenges on days 11–13 (n=6 mice per group). Limonene was administered as an inhalation prior to allergen challenges in one group of allergic mice for both WT and KO (SEN+LIM). Whole body plethysmography (measuring airway responsiveness as enhanced pause, Penh) and bronchoalveolar lavage (BAL) studies were performed. Airway responsiveness to MCh (48 mg/ml) in WT SEN group was significantly lowered with limonene treatment (420±92.57% in SEN vs. 56.23±25% in SEN+LIM). However, limonene did not have an effect in A2AKO (553±85% in SEN vs. 588±34% in SEN+LIM). NECA‐induced increased airway responsiveness was attenuated in limonene‐treated WT SEN mice (1002±161 in SEN vs. 250±226%, p<0.05) while no effect was observed in A2AKO groups (541±44% in SEN vs. 528±147% in SEN+LIM). Differential BAL cell analysis showed that limonene reduced levels of eosinophils in WT SEN (70.66±2.6% in SEN vs. 28.66±1.45% in SEN+LIM, p<0.05) while no difference was observed in A2AKO (76.33±1.35% in SEN vs 79±0.69% in SEN+LIM). These data suggest that limonene‐induced reduction in airway inflammation and airway reactivity occurs via activation of A2AAR.Support or Funding InformationLong Island University start‐up funding (DSP)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.