TY - JOUR
T1 - The activin A antagonist follistatin inhibits asthmatic airway remodelling
AU - Hardy, Charles Linton
AU - Nguyen, Hong-An Thi
AU - Mohamud, Rohimah
AU - Yao, Jun John
AU - Oh, Ding Yuan
AU - Plebanski, Magdalena
AU - Loveland, Katherine Ann Lakoski
AU - Harrison, Craig
AU - Rolland, Jennifer May
AU - O'Hehir, Robyn E
PY - 2013
Y1 - 2013
N2 - 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)-?? 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 I?g) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-??1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-??1 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. Copyright Article author (or their employer) 2012.
AB - 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)-?? 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 I?g) inhibited the airway remodelling and dose-dependently decreased airway activin A and TGF-??1, and allergen-specific T helper 2 cytokine production in the lung-draining lymph nodes. Follistatin also impaired the loss of TGF-??1 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. Copyright Article author (or their employer) 2012.
UR - http://thorax.bmj.com/content/68/1/9.full.pdf+html
U2 - 10.1136/thoraxjnl-2011-201128
DO - 10.1136/thoraxjnl-2011-201128
M3 - Article
SN - 0040-6376
VL - 68
SP - 9
EP - 18
JO - Thorax
JF - Thorax
IS - 1
ER -