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
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
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Skipp, Paul
1ba7dcf6-9fe7-4b5c-a9d0-e32ed7f42aa5
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Marshall, B.
c1438a0d-f075-4eb6-806d-7926401fbf00
Fletcher, Sophie
d05721e8-8943-4f13-a1f5-4ba183741c89
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Johnson, Benjamin
dce3d588-86b3-4647-a871-1b0408b456bb
30 June 2020
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
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Skipp, Paul
1ba7dcf6-9fe7-4b5c-a9d0-e32ed7f42aa5
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Marshall, B.
c1438a0d-f075-4eb6-806d-7926401fbf00
Fletcher, Sophie
d05721e8-8943-4f13-a1f5-4ba183741c89
Richeldi, Luca
47177d9c-731a-49a1-9cc6-4ac8f6bbbf26
Johnson, Benjamin
dce3d588-86b3-4647-a871-1b0408b456bb
Conforti, Franco, Ridley, Robert, Brereton, Christopher J, Jones, Mark, Davies, Donna, Skipp, Paul, Wang, Yihua, Ottensmeier, Christian, Richeldi, Luca and Johnson, Benjamin
,
et al.
(2020)
Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis.
Cell Death and Discovery, 6, [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
Text
s41420-020-0289-9
- Version of Record
More information
Accepted/In Press date: 8 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
Catalogue record
Date deposited: 06 Jul 2020 16:30
Last modified: 17 Mar 2024 05:39
Export record
Altmetrics
Contributors
Author:
Franco Conforti
Author:
Robert Ridley
Author:
Christopher J Brereton
Author:
Aiman Alzetani
Author:
B. Marshall
Author:
Sophie Fletcher
Author:
Luca Richeldi
Author:
Benjamin Johnson
Corporate Author: et al.
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
