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).
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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- Faculties (pre 2018 reorg) > Faculty of Natural and Environmental Sciences (pre 2018 reorg) > Institute for Life Sciences (pre 2018 reorg)
Current Faculties > Faculty of Environmental and Life Sciences > Institute for Life Sciences > Institute for Life Sciences (pre 2018 reorg)
Institute for Life Sciences > Institute for Life Sciences (pre 2018 reorg) - Current Faculties > Faculty of Medicine > Clinical and Experimental Sciences > Respiratory
Clinical and Experimental Sciences > Respiratory - Faculties (pre 2018 reorg) > Faculty of Engineering and the Environment (pre 2018 reorg) > Southampton Marine & Maritime Institute (pre 2018 reorg)
- Faculties (pre 2018 reorg) > Faculty of Medicine (pre 2018 reorg) > Clinical & Experimental Sciences (pre 2018 reorg)
Current Faculties > Faculty of Medicine > Clinical and Experimental Sciences > Clinical & Experimental Sciences (pre 2018 reorg)
Clinical and Experimental Sciences > Clinical & Experimental Sciences (pre 2018 reorg) - Current Faculties > Faculty of Environmental and Life Sciences > School of Biological Sciences > Developmental Biology
School of Biological Sciences > Developmental Biology - Current Faculties > Faculty of Medicine > Cancer Sciences
Cancer Sciences - Current Faculties > Faculty of Medicine > Clinical and Experimental Sciences
Clinical and Experimental Sciences - Current Faculties > Faculty of Environmental and Life Sciences > School of Biological Sciences > Computational and Systems Biology
School of Biological Sciences > Computational and Systems Biology
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