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Differential Effects of Limonene on Inflammation via Activation of A 2A and A 2B Adenosine Receptors in Asthma
Author(s) -
Rajalingam Sahith,
Patel Mehaben,
Bhavsar Riyakumar,
Frey Kathleen,
Ahmad Mirvice,
Mustafa S Jamal,
Ledent Catherine,
Ponnoth Dovenia S
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.681.5
Subject(s) - ovalbumin , adenosine receptor , chemistry , agonist , receptor , inflammation , allergic inflammation , pharmacology , immunology , limonene , allergen , medicine , endocrinology , biochemistry , allergy , immune system , chromatography , essential oil
Limonene a mono‐terpene flavonoid that is anti‐inflammatory in asthma. We have shown that limonene induces bronchodilation and lowers inflammation via A 2A receptor activation (FASEB J April 2017 31:820.1) in a mouse model of asthma. However, our data showed that limonene's effects on lowering neutrophils was occurring through a different pathway, as limonene reduced neutrophils in the absence of the A 2A receptor. We hypothesized that limonene may also activate A 2B receptors based on its similar binding interactions with both A 2A AR and A 2B AR using a structural homology model. We investigated the effects of limonene on lung inflammation and airway reactivity in A 2A AR knock‐out (A 2A KO) 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 0.2μg 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). The role of A 2B receptors was studied by treating SEN A 2A KO mice with BAY 606583 (selective A 2B agonist; 150mg/kg i.p.). 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 A 2A KO (76.33±1.35% in SEN vs 79±0.69% in SEN+LIM). However, neutrophils were significantly lowered in A 2A KO (from 19±1.02 in SEN A 2A KO to 10±0.4 in SEN+LIM) in BAL. SEN A 2A KO treated with BAY 606583 showed similar reduction in the number of neutrophils (10±2.1%) compared to A 2A KO SEN treated with limonene (10±0.4). No significant difference was seen in other inflammatory cells sensitized A 2A KO mice treated with BAY606583. Tracheal ring reactivity was also studied using isolated organ bath system. Contraction to methacholine (MCh; 0.1μM) in isolated trachea was significantly higher in SEN tissues (225.99±67.34% vs 5.57±19.74% in CON). Treatment with limonene significantly reduced the tracheal reactivity (80.68±20% in SEN+LIM vs SEN; p<0.05). In A 2A KO tissues, limonene did not have any effect to reduce MCh reactivity. SCH58651(A 2A receptor antagonist) blunted the effects of limonene on tracheal reactivity. CGS‐21680 (A 2A receptor agonist) had very little effect on tracheal relaxation in SEN WT tissue while SEN+LIM trachea had relaxation to CGS 21680. These data suggest that limonene reduces tracheal reactivity to MCh and eosinophilia via an A 2A AR‐dependent pathway, while reduction in airway neutrophilia occurs vai an A 2B AR‐dependent pathway. Support or Funding Information Institutional Grant, Long Island UniversityD‐limonene binds to A2A adenosine receptor (A2AAR) and decreases the eosinophilia and airway hyper reactivity induced by methacholine. In the absence of A2AAR (A2AKO), d‐limonene can bind to A2BAR and decreases airway neutrophil count in bronchoalveolar lavageThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .