Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor.
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 Ca2+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.
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.
Tongde
T
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.|Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Julianne
J
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
PJ
Moore
Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Michael S
MS
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
WG
Walton
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 C
RC
Fellner
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.
Neil E
NE
Alexis
Department of Environmental and Occupational Health, University of Pittsburgh, 331 Bridgeside Point Building, Pittsburgh, Pennsylvania 15260, USA.
Y
Y
Peter Di
Department of Chemistry, Genome Science Building, 250 Bell Tower Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Matthew R
MR
Redinbo
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.|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.
Stephen L
SL
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.|Department of Cell Biology &Physiology, 5200 Medical Biomolecular Research Building, 111 Mason Farm Road, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7248, USA.
Robert
R
Tarran
D000328:Adult; D000368:Aged; D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D001980:Bronchi / Q000166:cytology; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000737:chemistry / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D062105:Molecular Docking Simulation; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000503:physiopathology*; D000071740:ORAI1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology; D013183:Sputum / Q000502:physiology; D055815:Young Adult
C485599:BPIFA1 protein, human; C119074:Bpifa1 protein, mouse; D006023:Glycoproteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins