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Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor

Author

Listed:
  • Tongde Wu

    (Cystic Fibrosis Center/Marsico Lung Institute)

  • Julianne Huang

    (Cystic Fibrosis Center/Marsico Lung Institute
    Genome Science Building)

  • 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
    Center for Environmental Medicine, Asthma, and Lung Biology, US EPA Human Studies Facility)

  • Robert Tarran

    (Cystic Fibrosis Center/Marsico Lung Institute
    Department of Cell Biology & Physiology)

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.

Suggested Citation

  • 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, 2017. "Identification of BPIFA1/SPLUNC1 as an epithelium-derived smooth muscle relaxing factor," Nature Communications, Nature, vol. 8(1), pages 1-10, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14118
    DOI: 10.1038/ncomms14118
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