Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor.
Tongde Wu, Julianne Huang, Patrick J Moore, Michael S Little, William G Walton, Robert C Fellner, Neil E Alexis, Y Peter Di, Matthew R Redinbo, Stephen L Tilley, Robert Tarran
Author Information
Tongde Wu: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Julianne Huang: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Patrick J Moore: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Michael S Little: Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
William G Walton: Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Robert C Fellner: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Neil E Alexis: Center for Environmental Medicine, Asthma, and Lung Biology, US EPA Human Studies Facility, 104 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Y Peter Di: Department of Environmental and Occupational Health, University of Pittsburgh, 331 Bridgeside Point Building, Pittsburgh, Pennsylvania 15260, USA.
Matthew R Redinbo: Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Stephen L Tilley: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Robert Tarran: Cystic Fibrosis Center/Marsico Lung Institute, Marsico Hall, 125 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Asthma is a chronic airway disease characterized by inflammation, mucus hypersecretion and abnormal airway smooth muscle (ASM) contraction. Bacterial permeability family member A1, BPIFA1, is a secreted innate defence protein. Here we show that BPIFA1 levels are reduced in sputum samples from asthmatic patients and that BPIFA1 is secreted basolaterally from healthy, but not asthmatic human bronchial epithelial cultures (HBECs), where it suppresses ASM contractility by binding to and inhibiting the Ca influx channel Orai1. We have localized this effect to a specific, C-terminal α-helical region of BPIFA1. Furthermore, tracheas from Bpifa1 mice are hypercontractile, and this phenotype is reversed by the addition of recombinant BPIFA1. Our data suggest that BPIFA1 deficiency in asthmatic airways promotes Orai1 hyperactivity, increased ASM contraction and airway hyperresponsiveness. Strategies that target Orai1 or the BPIFA1 deficiency in asthma may lead to novel therapies to treat this disease.
