Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis
Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis
Idiopathic pulmonary fibrosis (IPF) is a chronic scarring disease in which aging, environmental exposure(s) and genetic susceptibility have been implicated in disease pathogenesis, however, the causes and mechanisms of the progressive fibrotic cascade are still poorly understood. As epithelial–mesenchymal interactions are essential for normal wound healing, through human 2D and 3D in vitro studies, we tested the hypothesis that IPF fibroblasts (IPFFs) dysregulate alveolar epithelial homeostasis. Conditioned media from IPFFs exaggerated the wound-healing response of primary human Type II alveolar epithelial cells (AECs). Furthermore, AECs co-cultured with IPFFs exhibited irregular epithelialization compared with those co-cultured with control fibroblasts (NHLFs) or AECs alone, suggesting that epithelial homeostasis is dysregulated in IPF as a consequence of the abnormal secretory phenotype of IPFFs. Secretome analysis of IPFF conditioned media and functional studies identified the matricellular protein, SPARC, as a key mediator in the epithelial–mesenchymal paracrine signaling, with increased secretion of SPARC by IPFFs promoting persistent activation of alveolar epithelium via an integrin/focal adhesion/cellular-junction axis resulting in disruption of epithelial barrier integrity and increased macromolecular permeability. These findings suggest that in IPF fibroblast paracrine signaling promotes persistent alveolar epithelial activation, so preventing normal epithelial repair responses and restoration of tissue homeostasis. Furthermore, they identify SPARC-mediated paracrine signaling as a potential therapeutic target to promote the restoration of lung epithelial homoestasis in IPF patients.
Conforti, Franco
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Ridley, Robert
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Brereton, Christopher J
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Alzetani, Aiman
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Jones, Mark
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Davies, Donna
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Skipp, Paul
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Wang, Yihua
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Ottensmeier, Christian
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Marshall, B.
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Fletcher, S.
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Richeldi, Luca
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Johnson, Benjamin
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30 June 2020
Conforti, Franco
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Ridley, Robert
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Brereton, Christopher J
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Alzetani, Aiman
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Jones, Mark
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Davies, Donna
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Skipp, Paul
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Wang, Yihua
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Ottensmeier, Christian
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Marshall, B.
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Fletcher, S.
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Richeldi, Luca
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Johnson, Benjamin
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Conforti, Franco, Ridley, Robert, Brereton, Christopher J, Alzetani, Aiman, Jones, Mark, Davies, Donna, Skipp, Paul, Wang, Yihua, Ottensmeier, Christian, Marshall, B., Fletcher, S., Richeldi, Luca and Johnson, Benjamin
(2020)
Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis.
Cell Death and Discovery, 6 (1), [54].
(doi:10.1038/s41420-020-0289-9).
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic scarring disease in which aging, environmental exposure(s) and genetic susceptibility have been implicated in disease pathogenesis, however, the causes and mechanisms of the progressive fibrotic cascade are still poorly understood. As epithelial–mesenchymal interactions are essential for normal wound healing, through human 2D and 3D in vitro studies, we tested the hypothesis that IPF fibroblasts (IPFFs) dysregulate alveolar epithelial homeostasis. Conditioned media from IPFFs exaggerated the wound-healing response of primary human Type II alveolar epithelial cells (AECs). Furthermore, AECs co-cultured with IPFFs exhibited irregular epithelialization compared with those co-cultured with control fibroblasts (NHLFs) or AECs alone, suggesting that epithelial homeostasis is dysregulated in IPF as a consequence of the abnormal secretory phenotype of IPFFs. Secretome analysis of IPFF conditioned media and functional studies identified the matricellular protein, SPARC, as a key mediator in the epithelial–mesenchymal paracrine signaling, with increased secretion of SPARC by IPFFs promoting persistent activation of alveolar epithelium via an integrin/focal adhesion/cellular-junction axis resulting in disruption of epithelial barrier integrity and increased macromolecular permeability. These findings suggest that in IPF fibroblast paracrine signaling promotes persistent alveolar epithelial activation, so preventing normal epithelial repair responses and restoration of tissue homeostasis. Furthermore, they identify SPARC-mediated paracrine signaling as a potential therapeutic target to promote the restoration of lung epithelial homoestasis in IPF patients.
Text
Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis
- Accepted Manuscript
More information
Accepted/In Press date: 8 June 2020
e-pub ahead of print date: 30 June 2020
Published date: 30 June 2020
Additional Information:
Funding Information:
F.C. was supported by the Medical Research Foundation (MRF-091-0003-RG-CONFO); Y.W. was supported by Medical Research Council (MR/S025480/1) and an Academy of Medical Sciences/the Wellcome Trust Springboard Award (SBF002\1038). We thank the Staff of the Biomedical Imaging Unit for assistance with confocal microscopy and the NIHR Southampton Biomedical Research Centre (Respiratory and critical care theme) and the Wellcome Trust Clinical Research Facility for clinical support.
Publisher Copyright:
© 2020, The Author(s).
Identifiers
Local EPrints ID: 442025
URI: http://eprints.soton.ac.uk/id/eprint/442025
ISSN: 2058-7716
PURE UUID: fd82bb58-5014-43c1-abce-c9dd2ae11eef
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Date deposited: 06 Jul 2020 16:30
Last modified: 05 Oct 2022 04:02
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Contributors
Author:
Franco Conforti
Author:
Robert Ridley
Author:
Christopher J Brereton
Author:
Aiman Alzetani
Author:
B. Marshall
Author:
S. Fletcher
Author:
Luca Richeldi
Author:
Benjamin Johnson
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