The activin A antagonist follistatin inhibits asthmatic airway remodelling.
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.
Department of Immunology, Monash University, Melbourne, Victoria, Australia. charles.hardy@monash.edu
Charles Linton
CL
Hardy
Hong-An
HA
Nguyen
Rohimah
R
Mohamud
John
J
Yao
Ding Yuan
DY
Oh
Magdalena
M
Plebanski
Kate L
KL
Loveland
Craig A
CA
Harrison
Jennifer M
JM
Rolland
Robyn E
RE
O'Hehir
D028341:Activins / Q000037:antagonists & inhibitors*; D000281:Administration, Intranasal; D056151:Airway Remodeling / Q000187:drug effects* / Q000276:immunology; D000704:Analysis of Variance; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D038681:Follistatin / Q000276:immunology / Q000494:pharmacology*; D007150:Immunohistochemistry; D018793:Interleukin-13 / Q000032:analysis / Q000378:metabolism; D015847:Interleukin-4 / Q000032:analysis / Q000378:metabolism; D015848:Interleukin-5 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology / Q000378:metabolism; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*
D016207:Cytokines; D038681:Follistatin; D018793:Interleukin-13; D015848:Interleukin-5; D016212:Transforming Growth Factor beta; C422405:activin A; D028341:Activins; D015847:Interleukin-4; D010047:Ovalbumin