TGF-β3 Promotes MUC5AC Hyper-Expression by Modulating Autophagy Pathway in Airway Epithelium

Mucus secretion accumulation in the airways may act as a contributing factor for the development of airflow limitation in severe fetal asthma patients. Accumulated evidences showed that transforming growth factor beta (TGF-beta 3) plays a regulatory role in airway remodeling including mucus hyper-secretion in asthma. However. the detailed molecular mechanisms of TGI-beta 3 induced MUC5AC hyper-expression in airway epithelium remains unclear. Here, we demonstrated the pivotal roles of autophagy in regulation of MUC5AC hyper-production induced by TGF-beta 3 in airway epithelium. Our experimental data showed that inhibiting autophagy pathway in repeated ovalbumin (OVA) exposed mice exhibited decreased airway hyper-response and airway inflammation, diminishing the expression of Muc5ac and TGF-beta 3. Furthermore, our studies demonstrated that autophagy was induced upon exposure to TGF-beta 3 and then mediated MUC5AC hyper-expression by activating the activator protein-1 (AP-1) in human bronchial epithelial cells. Finally, Smad2/3 pathway was involved in TGF-beta 3-induced MUC5AC hyper-expressions by promoting autophagy. These data indicated that autophagy was required for TGF beta 3 induced airway mucous hyper-production, and that inhibition of autophagy exerted therapeutic benefits for TGF-beta 3 induced airway mucus secretion. (C) 2018 The Authors. Published by Elsevier B.V.