Both transforming growth factor (TGF)-β1 and activin-A have been implicated in airway remodelling in asthma but the modulation of their specific signalling pathways after disease activation remains undefined.
To define the expression kinetics of TGF-β1, activin-A ligands and follistatin (a natural activin inhibitor), their Type I and Type II receptors (ALK-1, ALK-5 and ALK-4 and TβRII and ActRIIA/RIIB) and activation of signalling (via pSmad2), in the asthmatic airway following allergen challenge.
Immunohistochemistry was performed on bronchial biopsies from 15 mild atopic asthmatics (median age 25 years, median FEV1% predicted 97%) at baseline and 24 hours after allergen inhalation. Functional effects of activin-A were evaluated using cultured normal human bronchial epithelial (NHBE) cells.
pSmad2+ epithelial cells increased at 24 hours (p=0.03) and pSmad2 was detected in submucosal cells. No modulation of activin-A, follistatin or TGF-β1 expression was demonstrated. Activin receptor+ cells increased after allergen challenge.: ALK-4 in epithelium (p=0.04) and submucosa (p=0.04), and ActRIIA in epithelium (p=0.01). The TGF-β receptor ALK-5 expression was minimal in the submucosa at baseline and after challenge and was down-regulated in the epithelium after challenge (p=0.02), whereas ALK-1 and TβRII expression in the submucosa increased after allergen challenge (p=0.03 and p=0.004 respectively). ALK-1 and ALK-4 expression by T cells was increased after allergen challenge. Activin-A induced NHBE cell proliferation, was produced by NHBE cells in response to TNF-α, and down-regulated TNF-α and IL-13-induced chemokine production by NHBE cells.
Both TGF-β and activin signalling pathways are activated upon allergen provocation in asthma. Activin-A may contribute to resolution of inflammation.