Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin‐1c

• Published in: The Journal of pathology Vol. 243; no. 4; pp. 510 - 523
• Main Authors: Liu, Gang, Cooley, Marion A, Nair, Prema M, Donovan, Chantal, Hsu, Alan C, Jarnicki, Andrew G, Haw, Tatt Jhong, Hansbro, Nicole G, Ge, Qi, Brown, Alexandra C, Tay, Hock, Foster, Paul S, Wark, Peter A, Horvat, Jay C, Bourke, Jane E, Grainge, Chris L, Argraves, W Scott, Oliver, Brian G, Knight, Darryl A, Burgess, Janette K, Hansbro, Philip M
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.12.2017; Wiley Subscription Services, Inc
• Subjects: Actin; Actins - metabolism; airway hyperresponsiveness; Airway Remodeling; airway remodelling; allergic airway disease; Animals; Asthma; Asthma - immunology; Asthma - metabolism; Asthma - physiopathology; Asthma - prevention & control; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - metabolism; Bronchial Hyperreactivity - physiopathology; Bronchial Hyperreactivity - prevention & control; Bronchoconstriction; Calcium-Binding Proteins - deficiency; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Cells, Cultured; Clonal deletion; Coculture Techniques; Collagen; Cytokines - genetics; Cytokines - metabolism; Dendritic cells; Disease Models, Animal; Epithelial cells; Extracellular matrix; Extracellular Matrix Proteins - deficiency; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibronectin; fibrosis; fibulin‐1; GATA-3 protein; Genotype; Helper cells; House dust; Humans; inflammation; Inflammation - immunology; Inflammation - metabolism; Inflammation - physiopathology; Inflammation - prevention & control; Inflammation Mediators - metabolism; Interleukin 13; Interleukin 5; Lung - immunology; Lung - metabolism; Lung - physiopathology; lung function; Lungs; Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - metabolism; Lymphatic system; Lymphocytes; Lymphocytes T; Matrix protein; Mice; Mice, Inbred C57BL; Mice, Knockout; mRNA; Mucin; Muscle contraction; Phenotype; Proteins; Respiratory tract diseases; RNA Interference; Rodents; Signal Transduction; Smooth muscle; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Therapeutic targets; Time Factors; Transfection; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; United Kingdom > UK; Ireland; allergic airway disease; airway hyperresponsiveness; fibulin-1; lung function; inflammation; airway remodelling; collagen; asthma; fibrosis
• DOI: 10.1002/path.4979
• ISSN: 0022-3417

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.