Blocking Notch3 Signaling Abolishes MUC5AC Production in Airway Epithelial Cells from Individuals with Asthma

• DOI: 10.1165/rcmb.2019-0069oc
• Publication Date: 2020-01-10T19:35:06Z
• Authors: Andrew T. Reid; Kristy S. Nichol; Punnam Chander Ve...; Fatemeh Moheimani; Anthony Kicic; Stephen M. Stick; Nathan W. Bartlett; Chris L. Grainge; Peter A. B. Wark; Philip M. Hansbro; Darryl A. Knight
• Keywords: Male; 0301 basic medicine; Sustainable Development Goals; 610; Bronchi; Respiratory Mucosa; Mucin 5AC; 03 medical and health sciences; mucus; pharmacological inhibition; Humans; RNA, Small Interfering; Lung; Receptor, Notch3; Cells, Cultured; SDG 3; Aged; airway epithelium; Cell Differentiation; Epithelial Cells; Middle Aged; MUC5AC; notch signaling; Asthma; 3. Good health; Female; Goblet Cells; Signal Transduction

In asthma, goblet cell numbers are increased within the airway epithelium, perpetuating production of mucus that is more difficult to clear and results in plugging. Notch1, Notch2, or Notch3, a combination these has been shown influence differentiation epithelial cells. How expression specific Notch isoforms differs fully differentiated adult asthmatic epithelium whether influences mucin after currently unknown. We aimed quantify different individuals with severe asthma examine impact signaling on MUC5AC. Human lung sections primary bronchial cells from without were used this study. Primary at air-liquid interface for 28 days. isoform was analyzed by Taqman quantitative PCR. Immunohistochemistry localize human sections. inhibited vitro using dibenzazepine Notch3-specific siRNA, followed analysis NOTCH3 highly expressed compared nonasthmatic epithelium. Dibenzazepine significantly reduced MUC5AC cultures concomitantly suppression intracellular domain protein. Specific knockdown siRNA recapitulated dibenzazepine-induced reduction demonstrate regulator production. Increased may therefore be an underlying driver excess