Mast Cell Phenotype, Location, and Activation in Severe Asthma

Abstract

Rationale: Severe asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity. Objectives: To compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant parameters between normal subjects and subjects with asthma to clarify their pathobiologic importance. Methods: Endobronchial biopsies, epithelial brushings, and bronchoalveolar lavage were obtained from subjects with asthma and normal subjects from the Severe Asthma Research Program (N 5 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MC Tot ) and the MC TC subset (MCs positive for both tryptase and chymase) using immunostaining and quantitative real-time polymerase chain reaction. Lavage was analyzed for tryptase and prostaglandin D2 (PGD2) by ELISA. Measurements and Main Results: Submucosal MC Tot (tryptase-positive by immunostaining) numbers were highest in ''mild asthma/no inhaled corticosteroid (ICS) therapy'' subjects and decreased with greater asthma severity (P 5 0.002). In contrast, MC TC (chymasepositive by immunostaining) were the predominant (MC TC /MC Tot . 50%) MC phenotype in SA (overall P 5 0.005). Epithelial MC Tot were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MC TC . Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P 5 0.008 and P 5 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P 5 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MC TC /MC Tot predicted SA. Conclusions: Severe asthma is associated with a predominance of MC TC in the airway submucosa and epithelium. Activation of those MC TC may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

“…Inflammation associated with high expression of Th2 cytokines has also been linked to mast cells [63]. Mast cells are increased in airway smooth muscle and epithelial compartments in asthma where they have been linked to poor asthma control and airway hyperresponsiveness [64,65].…”

Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias

“…Our previous studies showed accumulation of mast cells in the airways of severe asthmatics (31), and more recently, they were detected in the sputum of subjects with persistent asthma (32). Their recruitment to ASMs in the airways of asthmatics was shown to require CXCR3 expressed by the cells (17).…”

“…Samples used were from patients from SARP I/II had who previously undergone fiberoptic bronchoscopy with BAL using a previously published protocol (31). Recovered fluid was centrifuged to obtain cells, and mRNA was extracted as described below.…”

High IFN-γ and low SLPI mark severe asthma in mice and humans

“…Subjects underwent extensive baseline characterization, including physiologic (spirometry, diffusing capacity, and PC20), allergic, and clinical characterization (47). Subjects also underwent bronchoscopy per published protocols and consistent with procedures practiced in the SA research program (48).…”