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 and Robert Tarran ()
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Tongde Wu: Cystic Fibrosis Center/Marsico Lung Institute
Julianne Huang: Cystic Fibrosis Center/Marsico Lung Institute
Patrick J. Moore: Cystic Fibrosis Center/Marsico Lung Institute
Michael S. Little: Genome Science Building
William G. Walton: Genome Science Building
Robert C. Fellner: Cystic Fibrosis Center/Marsico Lung Institute
Neil E. Alexis: Center for Environmental Medicine, Asthma, and Lung Biology, US EPA Human Studies Facility
Y. Peter Di: University of Pittsburgh
Matthew R. Redinbo: Genome Science Building
Stephen L. Tilley: Cystic Fibrosis Center/Marsico Lung Institute
Robert Tarran: Cystic Fibrosis Center/Marsico Lung Institute

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14118

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DOI: 10.1038/ncomms14118

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