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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Administration, Inhalation
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Allergens / administration & dosage
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Allergens / immunology*
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Animals
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Aspergillus fumigatus / chemistry*
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Aspergillus fumigatus / immunology
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Asthma / immunology*
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Asthma / pathology
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Bacterial Proteins / administration & dosage
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Bacterial Proteins / immunology*
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Bronchi / drug effects
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Bronchi / immunology
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Bronchi / pathology
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Bronchoconstriction / drug effects*
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Bronchoconstriction / immunology
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Calcium / immunology
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Calcium / metabolism
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Disease Models, Animal
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Endopeptidases / administration & dosage
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Endopeptidases / immunology*
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Extracellular Matrix / chemistry
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Extracellular Matrix / drug effects
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Extracellular Matrix / immunology
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Female
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Fungal Proteins / administration & dosage
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Fungal Proteins / immunology*
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Gene Expression
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Histamine / biosynthesis
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Histamine / immunology
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Humans
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Immunoglobulin E / biosynthesis*
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Mice
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Mice, Inbred BALB C
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Myocytes, Smooth Muscle / drug effects
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Myocytes, Smooth Muscle / immunology
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Myocytes, Smooth Muscle / pathology
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Primary Cell Culture
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Trachea / drug effects
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Trachea / immunology
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Trachea / pathology
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rho GTP-Binding Proteins / genetics
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rho GTP-Binding Proteins / immunology
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rhoA GTP-Binding Protein
Substances
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Allergens
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Bacterial Proteins
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Fungal Proteins
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Immunoglobulin E
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Histamine
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Endopeptidases
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alkaline protease
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RhoA protein, mouse
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rho GTP-Binding Proteins
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rhoA GTP-Binding Protein
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Calcium