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

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. BurgessPhilip M. Hansbro

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)510-523
Number of pages14
JournalJournal of Pathology
Volume243
Issue number4
DOIs
StatePublished - Dec 2017

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Airway Remodeling
Extracellular Matrix Proteins
Asthma
Inflammation
Pyroglyphidae
Interleukin-5
Collagen
Lung
Interleukin-13
Tumor Necrosis Factor-alpha
Lymph Nodes
Th2 Cells
fibulin
Mucins
Fibronectins
Dendritic Cells
Smooth Muscle
Actins
Cultured Cells
Chronic Disease

Keywords

  • airway hyperresponsiveness
  • airway remodelling
  • allergic airway disease
  • asthma
  • collagen
  • fibrosis
  • fibulin-1
  • inflammation
  • lung function

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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

In: Journal of Pathology, Vol. 243, No. 4, 12.2017, p. 510-523.

Research output: Contribution to journalArticle

Liu, G, Cooley, MA, Nair, PM, Donovan, C, Hsu, AC, Jarnicki, AG, Haw, TJ, Hansbro, NG, Ge, Q, Brown, AC, Tay, H, Foster, PS, Wark, PA, Horvat, JC, Bourke, JE, Grainge, CL, Argraves, WS, Oliver, BG, Knight, DA, Burgess, JK & Hansbro, PM 2017, 'Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c', Journal of Pathology, vol. 243, no. 4, pp. 510-523. https://doi.org/10.1002/path.4979
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. / Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c. In: Journal of Pathology. 2017 ; Vol. 243, No. 4. pp. 510-523.
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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.",
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AU - Liu, Gang

AU - Cooley, Marion A.

AU - Nair, Prema M.

AU - Donovan, Chantal

AU - Hsu, Alan C.

AU - Jarnicki, Andrew G.

AU - Haw, Tatt Jhong

AU - Hansbro, Nicole G.

AU - Ge, Qi

AU - Brown, Alexandra C.

AU - Tay, Hock

AU - Foster, Paul S.

AU - Wark, Peter A.

AU - Horvat, Jay C.

AU - Bourke, Jane E.

AU - Grainge, Chris L.

AU - Argraves, W. Scott

AU - Oliver, Brian G.

AU - Knight, Darryl A.

AU - Burgess, Janette K.

AU - Hansbro, Philip M.

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N2 - 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.

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KW - airway hyperresponsiveness

KW - airway remodelling

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KW - collagen

KW - fibrosis

KW - fibulin-1

KW - inflammation

KW - lung function

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