Increased density of intraepithelial mast cells in patients with exercise-induced bronchoconstriction regulated through epithelially derived thymic stromal lymphopoietin and IL-33.
BACKGROUND
Exercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect airway hyperresponsiveness. Mast cells are implicated in EIB, but the characteristics, regulation, and function of mast cells in patients with EIB are poorly understood.


OBJECTIVE
We sought to examine mast cell infiltration of the airway epithelium in patients with EIB and the regulation of mast cell phenotype and function by epithelially derived cytokines.


METHODS
Endobronchial biopsy specimens, epithelial brushings, and induced sputum were obtained from asthmatic patients with and without EIB and healthy control subjects. Mast cell proteases were quantified by using quantitative PCR, and mast cell density was quantified by using design-based stereology. Airway epithelial responses to wounding and osmotic stress were assessed in primary airway epithelial cells and ex vivo murine lung tissue. Mast cell granule development and function were examined in cord blood-derived mast cells.


RESULTS
Tryptase and carboxypeptidase A3 expression in epithelial brushings and epithelial mast cell density were selectively increased in the asthma group with EIB. An in vitro scratch wound initiated the release of thymic stromal lymphopoietin, which was greater in epithelial cells derived from asthmatic patients. Osmotic stress induced the release of IL-33 from explanted murine lungs, which was increased in allergen-treated mice. Thymic stromal lymphopoietin combined with IL-33 increased tryptase and carboxypeptidase A3 immunostaining in mast cell precursors and selectively increased cysteinyl leukotriene formation by mast cells in a manner that was independent of in vitro sensitization.


CONCLUSIONS
Mast cell infiltration of the epithelium is a critical determinant of indirect airway hyperresponsiveness, and the airway epithelium might serve as an important regulator of the development and function of this mast cell population.
Department of Medicine, Division of Pulmonary and Critical Care, University of Washington, Seattle, Wash.
Ying
Y
Lai
Department of Medicine, Division of Pulmonary and Critical Care, University of Washington, Seattle, Wash.
William A
WA
Altemeier
Department of Medicine, Division of Pulmonary and Critical Care, University of Washington, Seattle, Wash.
John
J
Vandree
Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Wash.
Adrian M
AM
Piliponsky
Department of Comparative Medicine, University of Washington, Seattle, Wash.
Brian
B
Johnson
Department of Comparative Medicine, University of Washington, Seattle, Wash.
Cara L
CL
Appel
Department of Comparative Medicine, University of Washington, Seattle, Wash.
Charles W
CW
Frevert
School of Veterinary Medicine, University of California Davis, Davis, Calif.
Dallas M
DM
Hyde
Immunology Program, Benaroya Research Institute, Seattle, Wash.
Steven F
SF
Ziegler
Department of Inflammation Research, Amgen, Seattle, Wash.
Dirk E
DE
Smith
Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, Wash.
William R
WR
Henderson
Department of Chemistry, University of Washington, Seattle, Wash; Department of Biochemistry, University of Washington, Seattle, Wash.
Michael H
MH
Gelb
Department of Medicine, Division of Pulmonary and Critical Care, University of Washington, Seattle, Wash. Electronic address: tealh@u.washington.edu.
Teal S
TS
Hallstrand
D000818:Animals; D001250:Asthma, Exercise-Induced / Q000276:immunology* / Q000473:pathology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D013183:Sputum / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D000094632:Thymic Stromal Lymphopoietin
Asthma; airway hyperresponsiveness; eicosanoid; epithelial cell; leukotriene