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Acute Allergen-Induced Airway Remodeling in Atopic Asthma

Allergy and Clinical Immunology, National Heart and Lung Institute, and Leukocyte Biology Section, Biomedical Sciences Division, Faculty of Medicine, Imperial College London, London, United Kingdom

Address correspondence to: Dr. A. B. Kay, Professor and Head, Allergy and Clinical Immunology, Imperial College London, National Heart and Lung Institute, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK. E-mail: a.b.kay{at}imperial.ac.uk

Studies in animals and in human atopic skin suggest that allergen challenge may activate acute tissue remodeling changes via transforming growth factor–ß 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–ß–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.

Abbreviations: antibody, Ab • airway hyperreactivity, AHR • alkaline phosphatase–antialkaline phosphatase, APAAP • airway smooth muscle, ASM • 4',6-diamidino-2-phenylindole, DAPI • extracellular matrix, ECM • epithelial mesenchymal trophic unit, EMTU • eosinophil cationic protein, EPC • heat shock protein, HSP • interleukin, IL • late asthmatic reaction, LAR • phosphorylated, phospho- • reticular BM, RBM • signal transducer and activator of transcription 6, STAT6 • transforming growth factor, TGF

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