title: Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo.
abstract: 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.
  
  
  OBJECTIVE
  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(A)Rs) are implicated in airway mucus. We examined the role of IL-13 and GABA(A)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 GABA(A)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 GABA(A)Rα2 in the MUC5AC pathway. Acetylcholine and α7-nAChRs might serve as therapeutic targets to control airway mucus.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA. msopori@lrri.org
authors.forename: Sravanthi
authors.initials: S
authors.lastname: Gundavarapu
authors.forename: Julie A
authors.initials: JA
authors.lastname: Wilder
authors.forename: Neerad C
authors.initials: NC
authors.lastname: Mishra
authors.forename: Jules
authors.initials: J
authors.lastname: Rir-Sima-Ah
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Langley
authors.forename: Shashi P
authors.initials: SP
authors.lastname: Singh
authors.forename: Ali Imran
authors.initials: AI
authors.lastname: Saeed
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jaramillo
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Gott
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Peña-Philippides
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Shilpa
authors.initials: S
authors.lastname: Buch
authors.forename: Mohan L
authors.initials: ML
authors.lastname: Sopori
mesh_terms: D000109:Acetylcholine / Q000502:physiology*; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology*; D004847:Epithelial Cells / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D018793:Interleukin-13 / Q000494:pharmacology; D008679:Metaplasia; D009093:Mucus / Q000166:cytology / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000502:physiology; D011978:Receptors, Nicotinic / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; D018793:Interleukin-13; D011963:Receptors, GABA-A; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D000109:Acetylcholine