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Publications

Journal Article Epublish 14 citations

PubMed: 34209854 DOI: 10.3390/cells10071628

Regulation of Cellular Senescence Is Independent from Profibrotic Fibroblast-Deposited ECM.

Cells 10(7)

Authors: Kaj E C Blokland, Habibie Habibie, Theo Borghuis, Greta J Teitsma, Michael Schuliga, Barbro N Melgert, Darryl A Knight, Corry-Anke Brandsma, Simon D Pouwels, Janette K Burgess

Affiliations

  • University of Groningen, University Medical Center Groningen, Department of Pathology and Medical Biology, 9713 GZ Groningen, The Netherlands.
  • University of Groningen, University Medical Center Groningen, Groningen Research Institute for Asthma and COPD, 9713 GZ Groningen, The Netherlands.
  • School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia.
  • National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis, Sydney, NSW 2050, Australia.
  • University of Groningen, Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, 9713 GZ Groningen, The Netherlands.
  • Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia.
  • Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Providence Health Care Research Institute, Vancouver, BC V6Z 1Y6, Canada.
  • Department of Pulmonology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with poor survival. Age is a major risk factor, and both alveolar epithelial cells and lung fibroblasts in this disease exhibit features of cellular senescence, a hallmark of ageing. Accumulation of fibrotic extracellular matrix (ECM) is a core feature of IPF and is likely to affect cell function. We hypothesize that aberrant ECM deposition augments fibroblast senescence, creating a perpetuating cycle favouring disease progression. In this study, primary lung fibroblasts were cultured on control and IPF-derived ECM from fibroblasts pretreated with or without profibrotic and prosenescent stimuli, and markers of senescence, fibrosis-associated gene expression and secretion of cytokines were measured. Untreated ECM derived from control or IPF fibroblasts had no effect on the main marker of senescence p16 and p21. However, the expression of alpha smooth muscle actin (ACTA2) and proteoglycan decorin (DCN) increased in response to IPF-derived ECM. Production of the proinflammatory cytokines C-X-C Motif Chemokine Ligand 8 (CXCL8) by lung fibroblasts was upregulated in response to senescent and profibrotic-derived ECM. Finally, the profibrotic cytokines transforming growth factor β1 (TGF-β1) and connective tissue growth factor (CTGF) were upregulated in response to both senescent- and profibrotic-derived ECM. In summary, ECM deposited by IPF fibroblasts does not induce cellular senescence, while there is upregulation of proinflammatory and profibrotic cytokines and differentiation into a myofibroblast phenotype in response to senescent- and profibrotic-derived ECM, which may contribute to progression of fibrosis in IPF.

MeSH

Growth, Cytokines, Cellular Senescence, Cells, Lung, Idiopathic Pulmonary Fibrosis, Extracellular Matrix, Fibroblasts

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