The activin A antagonist follistatin inhibits asthmatic airway remodelling.

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.

• Authors: Charles Linton Hardy, Hong-An Nguyen, Rohimah Mohamud, John Yao, Ding Yuan Oh, Magdalena Plebanski, Kate L Loveland, Craig A Harrison, Jennifer M Rolland, Robyn E O'Hehir
• Journal: Thorax (Thorax) Vol. 68 Issue 1 Pg. 9-18 (Jan 2013) ISSN: 1468-3296 [Electronic] England
• PMID: 23051972 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Follistatin
• Interleukin-13
• Interleukin-5
• Transforming Growth Factor beta
• activin A
• Activins
• Interleukin-4
• Ovalbumin

Topics

• Activins (antagonists & inhibitors)
• Administration, Intranasal
• Airway Remodeling (drug effects, immunology)
• Analysis of Variance
• Animals
• Asthma (drug therapy, immunology, pathology)
• Bronchoalveolar Lavage Fluid (cytology, immunology)
• Cytokines (analysis, metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Female
• Follistatin (immunology, pharmacology)
• Immunohistochemistry
• Interleukin-13 (analysis, metabolism)
• Interleukin-4 (analysis, metabolism)
• Interleukin-5 (analysis, metabolism)
• Mice
• Mice, Inbred BALB C
• Ovalbumin (immunology, metabolism)
• Random Allocation
• Reference Values
• Sensitivity and Specificity
• Transforming Growth Factor beta (analysis, metabolism)