Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c |
| |
| Authors: | Gang Liu Marion A Cooley Prema M Nair Chantal Donovan Alan C Hsu Andrew G Jarnicki Tatt Jhong Haw Nicole G Hansbro Qi Ge Alexandra C Brown Hock Tay Paul S Foster Peter A Wark Jay C Horvat Jane E Bourke Chris L Grainge W Scott Argraves Brian G Oliver Darryl A Knight Janette K Burgess Philip M Hansbro |
| |
| Institution: | 1. Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute and The University of Newcastle, Newcastle, New South Wales, Australia;2. Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA;3. Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Victoria, Australia;4. Woolcock Institute of Medical Research, Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia;5. Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, New South Wales, Australia;6. Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Parkville, Victoria, Australia;7. School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia;8. University of Groningen, University Medical Centre Groningen, Department of Pathology and Medical Biology, Groningen Research Institute of Asthma and COPD, Groningen, The Netherlands |
| |
| Abstract: | Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR). Asthma patients, in particular those with chronic or severe asthma, have airway remodelling that is associated with the accumulation of extracellular matrix (ECM) proteins, such as collagens. Fibulin‐1 (Fbln1) is an important ECM protein that stabilizes collagen and other ECM proteins. The level of Fbln1c, one of the four Fbln1 variants, which predominates in both humans and mice, is increased in the serum and airways fluids in asthma but its function is unclear. We show that the level of Fbln1c was increased in the lungs of mice with house dust mite (HDM)‐induced chronic allergic airway disease (AAD). Genetic deletion of Fbln1c and therapeutic inhibition of Fbln1c in mice with chronic AAD reduced airway collagen deposition, and protected against AHR. Fbln1c‐deficient (Fbln1c–/–) mice had reduced mucin (MUC) 5 AC levels, but not MUC5B levels, in the airways as compared with wild‐type (WT) mice. Fbln1c interacted with fibronectin and periostin that was linked to collagen deposition around the small airways. Fbln1c–/– mice with AAD also had reduced numbers of α‐smooth muscle actin‐positive cells around the airways and reduced airway contractility as compared with WT mice. After HDM challenge, these mice also had fewer airway inflammatory cells, reduced interleukin (IL)‐5, IL‐13, IL‐33, tumour necrosis factor (TNF) and CXCL1 levels in the lungs, and reduced IL‐5, IL‐33 and TNF levels in lung‐draining lymph nodes. Therapeutic targeting of Fbln1c reduced the numbers of GATA3‐positive Th2 cells in the lymph nodes and lungs after chronic HDM challenge. Treatment also reduced the secretion of IL‐5 and IL‐13 from co‐cultured dendritic cells and T cells restimulated with HDM extract. Human epithelial cells cultured with Fbln1c peptide produced more CXCL1 mRNA than medium‐treated controls. Our data show that Fbln1c may be a therapeutic target in chronic asthma. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| |
| Keywords: | asthma allergic airway disease fibulin‐1 collagen fibrosis airway remodelling inflammation lung function airway hyperresponsiveness |
|
|
