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

Sravanthi Gundavarapu, Julie A. Wilder, Neerad C. Mishra, Jules Rir-Sima-Ah, Raymond J. Langley, Shashi P. Singh, Ali Imran Saeed, Richard J. Jaramillo, Katherine M. Gott, Juan Carlos Peña-Philippides, Kevin S. Harrod, J. Michael McIntosh, Shilpa Buch, Mohan L. Sopori

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


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 (GABA ARs) are implicated in airway mucus. We examined the role of IL-13 and GABAARs 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 GABAAR 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 GABAARα2 in the MUC5AC pathway. Acetylcholine and α7-nAChRs might serve as therapeutic targets to control airway mucus.

Original languageEnglish (US)
Pages (from-to)770-780.e11
JournalJournal of Allergy and Clinical Immunology
Issue number3
StatePublished - Sep 2012


  • Cigarette smoke
  • acetylcholine
  • airway mucus
  • nicotine
  • nicotinic acetylcholine receptors
  • γ-aminobutyric acid receptors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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