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 J Buch, Mohan L. Sopori

Research output: Contribution to journalArticle

26 Citations (Scopus)

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. 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)
JournalJournal of Allergy and Clinical Immunology
Volume130
Issue number3
DOIs
StatePublished - Jan 1 2012

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Metaplasia
Nicotinic Receptors
Mucus
Hyperplasia
Nicotine
Interleukin-13
Tobacco Products
Epithelial Cells
Smoke
Acetylcholine
In Vitro Techniques
Allergens
Aminobutyrates
Interleukin-7
Picrotoxin
Tobacco Smoke Pollution
Muscarinic Antagonists
Airway Management
Ovalbumin
Muscarinic Receptors

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo. / Gundavarapu, Sravanthi; Wilder, Julie A.; Mishra, Neerad C.; Rir-Sima-Ah, Jules; Langley, Raymond J.; Singh, Shashi P.; Saeed, Ali Imran; Jaramillo, Richard J.; Gott, Katherine M.; Peña-Philippides, Juan Carlos; Harrod, Kevin S.; McIntosh, J. Michael; Buch, Shilpa J; Sopori, Mohan L.

In: Journal of Allergy and Clinical Immunology, Vol. 130, No. 3, 01.01.2012.

Research output: Contribution to journalArticle

Gundavarapu, S, Wilder, JA, Mishra, NC, Rir-Sima-Ah, J, Langley, RJ, Singh, SP, Saeed, AI, Jaramillo, RJ, Gott, KM, Peña-Philippides, JC, Harrod, KS, McIntosh, JM, Buch, SJ & Sopori, ML 2012, 'Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo', Journal of Allergy and Clinical Immunology, vol. 130, no. 3. https://doi.org/10.1016/j.jaci.2012.04.002
Gundavarapu, Sravanthi ; Wilder, Julie A. ; Mishra, Neerad C. ; Rir-Sima-Ah, Jules ; Langley, Raymond J. ; Singh, Shashi P. ; Saeed, Ali Imran ; Jaramillo, Richard J. ; Gott, Katherine M. ; Peña-Philippides, Juan Carlos ; Harrod, Kevin S. ; McIntosh, J. Michael ; Buch, Shilpa J ; Sopori, Mohan L. / Role of nicotinic receptors and acetylcholine in mucous cell metaplasia, hyperplasia, and airway mucus formation in vitro and in vivo. In: Journal of Allergy and Clinical Immunology. 2012 ; Vol. 130, No. 3.
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AU - Gundavarapu, Sravanthi

AU - Wilder, Julie A.

AU - Mishra, Neerad C.

AU - Rir-Sima-Ah, Jules

AU - Langley, Raymond J.

AU - Singh, Shashi P.

AU - Saeed, Ali Imran

AU - Jaramillo, Richard J.

AU - Gott, Katherine M.

AU - Peña-Philippides, Juan Carlos

AU - Harrod, Kevin S.

AU - McIntosh, J. Michael

AU - Buch, Shilpa J

AU - Sopori, Mohan L.

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N2 - 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.

AB - 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.

KW - Cigarette smoke

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