Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo

• Published in: Journal of allergy and clinical immunology 2012-09, Vol.130 (3), p.770-780.e11
• Main Authors: Gundavarapu, Sravanthi, MS, Wilder, Julie A., PhD, Mishra, Neerad C., PhD, Rir-sima-ah, Jules, MS, Langley, Raymond J., PhD, Singh, Shashi P., PhD, Saeed, Ali Imran, MD, Jaramillo, Richard J., BS, Gott, Katherine M., BS, Peña-Philippides, Juan Carlos, BS, Harrod, Kevin S., PhD, McIntosh, J. Michael, PhD, Buch, Shilpa, PhD, Sopori, Mohan L., PhD
• Format: Article
• Language: English
• Subjects: acetylcholine; Acetylcholine - physiology; Acetylcholine receptors; airway mucus; Allergy and Immunology; alpha7 Nicotinic Acetylcholine Receptor; Biological and medical sciences; Bronchi - pathology; Bronchi - secretion; Cigarette smoke; Epithelial Cells - pathology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Hyperplasia; Immunopathology; Interleukin-13 - pharmacology; Medical sciences; Metaplasia; Mucus - cytology; Mucus - physiology; nicotine; Nicotine - pharmacology; nicotinic acetylcholine receptors; Receptors, GABA-A - physiology; Receptors, Nicotinic - physiology; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Tobacco, tobacco smoking; Toxicology; γ-aminobutyric acid receptors
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2012.04.002

Background Airway mucus hypersecretion is a key pathophysiologic feature in a number of lung diseases. Cigarette smoke/nicotine and allergens are strong stimulators of airway mucus; however, the mechanism of mucus modulation is unclear. Objectives We sought to characterize the pathway by which cigarette smoke/nicotine regulates airway mucus and identify agents that decrease airway mucus. Methods IL-13 and γ-aminobutyric acid type A receptors (GABAA Rs) are implicated in airway mucus. We examined the role of IL-13 and GABAA Rs in nicotine-induced mucus formation in normal human bronchial epithelial (NHBE) and A549 cells and secondhand cigarette smoke–induced, ovalbumin-induced, or both mucus formation in vivo. Results Nicotine promotes mucus formation in NHBE cells; however, the nicotine-induced mucus formation is independent of IL-13 but sensitive to the GABAA R antagonist picrotoxin. Airway epithelial cells express α7-, α9-, and α10-nicotinic acetylcholine receptors (nAChRs), and specific inhibition or knockdown of α7- but not α9/α10-nAChRs abrogates mucus formation in response to nicotine and IL-13. Moreover, addition of acetylcholine or inhibition of its degradation increases mucus in NHBE cells. Nicotinic but not muscarinic receptor antagonists block allergen- or nicotine/cigarette smoke–induced airway mucus formation in NHBE cells, murine airways, or both. Conclusions Nicotine-induced airway mucus formation is independent of IL-13, and α7-nAChRs are critical in airway mucous cell metaplasia/hyperplasia and mucus production in response to various promucoid agents, including IL-13. In the absence of nicotine, acetylcholine might be the biological ligand for α7-nAChRs to trigger airway mucus formation. α7-nAChRs are downstream of IL-13 but upstream of GABAA Rα2 in the MUC5AC pathway. Acetylcholine and α7-nAChRs might serve as therapeutic targets to control airway mucus.