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Paracrine SPARC signalling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis

Paracrine SPARC signalling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis
Paracrine SPARC signalling 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 to 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 signalling 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.
2058-7716
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
28bf123c-e42a-4fb5-8b26-f79e1095c586
Ridley, Robert
863f7655-4c32-47f8-8f04-76807a5bb63b
Brereton, Christopher J
948ca4ea-b04c-4b7a-bfe4-f79f184d7e43
Alzetani, Aiman
04d65796-5c8e-4c5b-aeeb-ea093c118f03
Jones, Mark
a6fd492e-058e-4e84-a486-34c6035429c1
Davies, Donna
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Skipp, Paul
1ba7dcf6-9fe7-4b5c-a9d0-e32ed7f42aa5
Wang, Yihua
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Ottensmeier, Christian
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Marshall, B.
c1438a0d-f075-4eb6-806d-7926401fbf00
Fletcher, S.
1a9b040d-eb68-40bb-90c1-7acceb095824
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Johnson, Benjamin
dce3d588-86b3-4647-a871-1b0408b456bb

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 signalling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis. Cell Death and Discovery, 6 (1), [54]. (doi:10.1038/s41420-020-0289-9).

Record type: Article

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 to 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 signalling 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.

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Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis - Accepted Manuscript
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Accepted/In Press date: 8 June 2020
e-pub ahead of print date: 30 June 2020

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Local EPrints ID: 442025
URI: http://eprints.soton.ac.uk/id/eprint/442025
ISSN: 2058-7716
PURE UUID: fd82bb58-5014-43c1-abce-c9dd2ae11eef
ORCID for Mark Jones: ORCID iD orcid.org/0000-0001-6308-6014
ORCID for Donna Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Paul Skipp: ORCID iD orcid.org/0000-0002-2995-2959
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 06 Jul 2020 16:30
Last modified: 18 Feb 2021 17:25

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Contributors

Author: Franco Conforti
Author: Robert Ridley
Author: Christopher J Brereton
Author: Aiman Alzetani
Author: Mark Jones ORCID iD
Author: Donna Davies ORCID iD
Author: Paul Skipp ORCID iD
Author: Yihua Wang ORCID iD
Author: B. Marshall
Author: S. Fletcher
Author: Luca Richeldi
Author: Benjamin Johnson

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