Acute allergen-induced airway remodeling in atopic asthma.
Studies in animals and in human atopic skin suggest that allergen challenge may activate acute tissue remodeling changes via transforming growth factor-beta pathways. We determined whether inhalational allergen challenge in subjects with mild asthma induces similar acute changes to the airway epithelial mesenchymal trophic unit (EMTU). Endobronchial mucosal biopsies obtained before and 24 h after challenge were examined by confocal microscopy for extracellular matrix deposition in the reticular basement membrane (RBM). Cells actively involved in extracellular matrix synthesis were identified as immunoreactive to heat shock protein 47, a chaperone of collagen synthesis. Interleukin-4/13 and transforming growth factor-beta-activated cells were identified by specific antibodies to phosphorylated (phospho-) signal transducer and activator of transcription 6 and phospho-Smad2, respectively. After allergen challenge, there was a significant increase in the number of heat shock protein 47-positive airway fibroblasts (P = 0.003) and in the thickness of tenascin in the RBM (P = 0.031). There were also increases in the number of phospho-Smad2+ epithelial cells (P = 0.04) and nuclear phospho-Smad2+ fibroblasts (P = 0.03), as well as phospho-signal transducer and activator of transcription 6+ epithelial cells (P = 0.03), after allergen challenge. Thus, allergen challenge in patients with mild asthma induces activation of epithelial cells and fibroblasts in the EMTU as well as increased tenascin deposition within the RBM. Airway remodeling in asthma may, in part, result from repeated acute activation of the EMTU by allergen exposure.
Phipps
Simon
S
Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK.
Benyahia
Farid
F
Ou
Tsan-Teng
TT
Barkans
Julia
J
Robinson
Douglas S
DS
Kay
A Barry
AB
D000485:Allergens / Q000187:drug effects / Q000276:immunology*; D001249:Asthma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001485:Basement Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001706:Biopsy; D003094:Collagen / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D050800:STAT6 Transcription Factor; D015843:Serpins / Q000378:metabolism; D051899:Smad2 Protein; D019063:Tenascin / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000485:Allergens; D004268:DNA-Binding Proteins; D050958:HSP47 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C494660:SERPINH1 protein, human; C497782:SMAD2 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015843:Serpins; D051899:Smad2 Protein; D019063:Tenascin; D015534:Trans-Activators; D003094:Collagen