title: A fungal protease allergen provokes airway hyper-responsiveness in asthma.
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.
authors: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
authors: Nariman A
authors: NA
authors: Balenga
authors: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, 125 South 31st Street, Philadelphia, Pennsylvania 19104-3413, USA.
authors: Michael
authors: M
authors: Klichinsky
authors: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
authors: Zhihui
authors: Z
authors: Xie
authors: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
authors: Eunice C
authors: EC
authors: Chan
authors: Protein Chemistry, Research Technologies Branch, Twinbrook I, 5640 Fishers Lane Room 1012 NIAID/NIH, Rockville, Maryland 20852-1737, USA.
authors: Ming
authors: M
authors: Zhao
authors: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, 125 South 31st Street, Philadelphia, Pennsylvania 19104-3413, USA.
authors: Joseph
authors: J
authors: Jude
authors: Institut universitaire de cardiologie et pneumologie de Québec (Laval University), Département multidisciplinaire de pneumologie et de chirurgie thoracique de l'IUCPQ, L35312725, chemin Sainte-Foy, Québec, Canada G1V 4G5.
authors: Michel
authors: M
authors: Laviolette
authors: Pulmonary, Allergy and Critical Care Division, Airways Biology Initiative, University of Pennsylvania, 125 South 31st Street, Philadelphia, Pennsylvania 19104-3413, USA.
authors: Reynold A
authors: RA
authors: Panettieri
authors: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID/NIH, 50 South Drive Room 4154, Bethesda, Maryland 20892-8305, USA.
authors: Kirk M
authors: KM
authors: Druey
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D001232:Aspergillus fumigatus / Q000737:chemistry* / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000276:immunology*; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016084:Bronchoconstriction / Q000187:drug effects* / Q000276:immunology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000008:administration & dosage / Q000276:immunology*; D005109:Extracellular Matrix / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D005260:Female; D005656:Fungal Proteins / Q000008:administration & dosage / Q000276:immunology*; D015870:Gene Expression; D006632:Histamine / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D061251:Primary Cell Culture; D014132:Trachea / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000276:immunology; D020742:rhoA GTP-Binding Protein
chemical_list: D000485:Allergens; D001426:Bacterial Proteins; D005656:Fungal Proteins; D007073:Immunoglobulin E; D006632:Histamine; D010450:Endopeptidases; C087822:alkaline protease; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium