Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program.
BACKGROUND
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.


OBJECTIVE
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 (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.


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 = 0.002). In contrast, MC(TC) (chymase-positive by immunostaining) were the predominant (MC(TC)/MC(Tot) > 50%) MC phenotype in SA (overall P = 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 = 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 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.
Balzar
Silvana
S
University of Pittsburgh Asthma Institute at UPMC/University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. balzars@upmc.edu
Fajt
Merritt L
ML
Comhair
Suzy A A
SA
Erzurum
Serpil C
SC
Bleecker
Eugene
E
Busse
William W
WW
Castro
Mario
M
Gaston
Benjamin
B
Israel
Elliot
E
Schwartz
Lawrence B
LB
Curran-Everett
Douglas
D
Moore
Charity G
CG
Wenzel
Sally E
SE
D000208:Acute Disease; D000328:Adult; D001249:Asthma / Q000209:etiology* / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002452:Cell Count; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D008875:Middle Aged; D010641:Phenotype; D015230:Prostaglandin D2 / Q000032:analysis / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
D015415:Biomarkers; D015230:Prostaglandin D2
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