Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 183, Issue 3, Pages 299-309Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201002-0295OC
Keywords
prostaglandin D2; chymase; carboxypeptidase A
Categories
Funding
- National Institute of Health, Children's Healthcare of Atlanta Center for Developmental Lung Biology [HL69116, HL69130, HL69155, HL69167, HL69170, HL69174, HL69349, HL091762, KL2RR025009, M01 RR02635, M01 RR03186, M01 RR007122-14, 1 UL1RR024153, 1 UL1RR024989, 1 UL1RR024992, 1 UL1RR025008, 1 UL1RR025011]
- National Institutes of Health (NIH) [T32 F32]
- Asthmatx
- NIH-NHLBI
- Electrocore
- BMS
- GlaxoSmithKline
- Pharming
- Novartis
- PhadiaNCU in royalties
- NIH
- Philip Morris Research Foundations
- Amira
- AstraZeneca
- Boehringer-Ingelheim
- Centocor
- Genentech
- Merck/Schering Plough
- Pfizer
- Wyeth
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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 = 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MCTot) and the MCTC 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 MCTot (tryptase-positive by immunostaining) numbers were highest in mild asthma/no inhaled corticosteroid (ICS) therapy subjects and decreased with greater asthma severity (P = 0.002). In contrast, MCTC (chymase-positive by immunostaining) were the predominant (MCTC/MCTot > 50%) MC phenotype in SA (overall P = 0.005). Epithelial MC-rot were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MCTC. Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P = 0.008 and P = 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P = 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MCTC/MCTot predicted SA. Conclusions: Severe asthma is associated with a predominance of MCTC in the airway submucosa and epithelium. Activation of those MCTC may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.
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