Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle ?2 Adrenoceptors.

ABSTRACT: Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. ?2 adrenoceptor (?2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to ?2-AR agonists would be attenuated when HLMCs are in contact with HASMCs. Cells were cultured in the presence of the short-acting ?2-agonist albuterol, and the long-acting ?2-agonists formoterol and olodaterol. Constitutive and Fc?RI-dependent HLMC histamine release, HASMC contraction, and ?2-AR phosphorylation at Tyr(350) were assessed. Constitutive HLMC histamine release was increased in HLMC-HASMC coculture and this was enhanced by ?2-AR agonists. Inhibition of Fc?RI-dependent HLMC mediator release by ?2-agonists was greatly reduced in HLMC-HASMC coculture. These effects were reversed by neutralization of stem cell factor (SCF) or cell adhesion molecule 1 (CADM1). ?2-AR agonists did not prevent HASMC contraction when HLMCs were present, but this was reversed by fluticasone. ?2-AR phosphorylation at Tyr(350) occurred within 5 min in both HLMCs and HASMCs when the cells were cocultured, and was inhibited by neutralizing SCF or CADM1. HLMC interactions with HASMCs via CADM1 and Kit inhibit the potentially beneficial effects of ?2-AR agonists on these cells via phosphorylation of the ?2-AR. These results may explain the potentially adverse effects of ?2-ARs agonists when used for asthma therapy. Targeting SCF and CADM1 may enhance ?2-AR efficacy, particularly in corticosteroid-resistant patients.

SUBMITTER: Lewis RJ 

PROVIDER: S-EPMC4685750 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature