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The activin A antagonist follistatin inhibits asthmatic airway remodelling
  1. Charles Linton Hardy1,2,3,
  2. Hong-An Nguyen1,2,3,
  3. Rohimah Mohamud1,3,
  4. John Yao1,2,3,
  5. Ding Yuan Oh1,2,
  6. Magdalena Plebanski1,3,
  7. Kate L Loveland4,
  8. Craig A Harrison5,
  9. Jennifer M Rolland1,2,3,
  10. Robyn E O'Hehir1,2,3
  1. 1Department of Immunology, Monash University, Melbourne, Victoria, Australia
  2. 2Department of Allergy, Immunology and Respiratory Medicine, Monash University and The Alfred Hospital, Melbourne, Victoria, Australia
  3. 3CRC for Asthma and Airways, Sydney, Australia
  4. 4Department of Biochemistry, Molecular Biology, Anatomy and Developmental Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia
  5. 5Growth Factor Signaling, Prince Henry's Institute, Clayton, Victoria, Australia
  1. Correspondence to Dr Charles Linton Hardy, Department of Immunology, Monash University, 89 Commercial Road, Level 2, Melbourne, VIC 3004, Australia; charles.hardy{at}monash.edu

Abstract

Background Current pharmacotherapy is highly effective in the clinical management of the majority of patients with stable asthma, however severe asthma remains inadequately treated. Prevention of airway remodelling is a major unmet clinical need in the management of patients with chronic severe asthma and other inflammatory lung diseases. Accumulating evidence convincingly demonstrates that activin A, a member of the transforming growth factor (TGF)-β superfamily, is a key driver of airway inflammation, but its role in chronic asthmatic airway remodelling is ill-defined. Follistatin, an endogenously produced protein, binds activin A with high affinity and inhibits its bioactivity. The aim of this study was to test the potential of follistatin as a therapeutic agent to inhibit airway remodelling in an experimental model of chronic allergic airway inflammation.

Methods BALB/c mice were systemically sensitised with ovalbumin (OVA), and challenged with OVA intranasally three times a week for 10 weeks. Follistatin was instilled intranasally during allergen challenge.

Results Chronic allergen challenge induced mucus hypersecretion and subepithelial collagen deposition which persisted after cessation of challenge. Intranasal follistatin (0.05, 0.5, 5 µg) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-β1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-β1 and activin RIB immunostaining in airway epithelium which occurred following chronic allergen challenge.

Conclusions These data demonstrate that follistatin attenuates asthmatic airway remodelling. Our findings point to the potential of follistatin as a therapeutic for prevention of airway remodelling in asthma and other inflammatory lung diseases.

  • Airway Epithelium
  • Allergic lung disease
  • Asthma
  • Cytokine Biology
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