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

Conforti, Franco, Ridley, Robert, Brereton, Christopher, Alzetani, Aiman, Johnson, Benjamin, Marshall, Ben G, Fletcher, Sophie V, Ottensmeier, Christian H ORCID: 0000-0003-3619-1657, Richeldi, Luca, Skipp, Paul
et al (show 3 more authors) (2020) Paracrine SPARC signaling dysregulates alveolar epithelial barrier integrity and function in lung fibrosis. CELL DEATH DISCOVERY, 6 (1). 54-.

Access the full-text of this item by clicking on the Open Access link.


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.

Item Type: Article
Uncontrolled Keywords: Experimental models of disease, Extracellular signalling molecules
Depositing User: Symplectic Admin
Date Deposited: 30 Jul 2020 13:28
Last Modified: 18 Jan 2023 23:39
DOI: 10.1038/s41420-020-0289-9
Open Access URL:
Related URLs: