Title: A fungal protease allergen provokes airway hyper-responsiveness in asthma.
Authors: Balenga, Nariman A; Klichinsky, Michael; Xie, Zhihui; Chan, Eunice C; Zhao, Ming; Jude, Joseph; Laviolette, Michel; Panettieri Jr, Reynold A; Druey, Kirk M
Published In Nat Commun, (2015 Apr 13)
Abstract: Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness.
PubMed ID: 25865874
MeSH Terms: Administration, Inhalation; Allergens/administration & dosage; Allergens/immunology*; Animals; Aspergillus fumigatus/chemistry*; Aspergillus fumigatus/immunology; Asthma/immunology*; Asthma/pathology; Bacterial Proteins/administration & dosage; Bacterial Proteins/immunology*; Bronchi/drug effects; Bronchi/immunology; Bronchi/pathology; Bronchoconstriction/drug effects*; Bronchoconstriction/immunology; Calcium/immunology; Calcium/metabolism; Disease Models, Animal; Endopeptidases/administration & dosage; Endopeptidases/immunology*; Extracellular Matrix/chemistry; Extracellular Matrix/drug effects; Extracellular Matrix/immunology; Female; Fungal Proteins/administration & dosage; Fungal Proteins/immunology*; Gene Expression; Histamine/biosynthesis; Histamine/immunology; Humans; Immunoglobulin E/biosynthesis*; Mice; Mice, Inbred BALB C; Myocytes, Smooth Muscle/drug effects; Myocytes, Smooth Muscle/immunology; Myocytes, Smooth Muscle/pathology; Primary Cell Culture; Trachea/drug effects; Trachea/immunology; Trachea/pathology; rho GTP-Binding Proteins/genetics; rho GTP-Binding Proteins/immunology; rhoA GTP-Binding Protein