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 pathophysiological feature in number of lung diseases. Cigarette smoke/nicotine and allergens are strong stimulators of airway mucus; however, the mechanism of mucus modulation is unclear. Objectives Characterize the pathway by which cigarette smoke/nicotine regulates airway mucus and identify agents that decrease airway mucus. Methods IL-13 and gamma-aminobutyric acid receptors (GABAARs) 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 and/or ovalbumin-induced 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 (PIC). Airway epithelial cells express α7/α9/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 and/or in mouse airways. 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 pro-mucoid agents, including IL-13. In the absence of nicotine, acetylcholine may 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 α-7-nAChRs may serve as therapeutic targets to control airway mucus.

Chronic electronic cigarette exposure in mice induces features of COPD in a nicotine-dependent manner

“…The airway epithelium expresses α3, α4, α5, α7, α9, β2 and β4 subunits for nAchRs,35 and their expression are highest on the apical cell surface, where exposure to inhaled nicotine occurs 36. In bronchiole cells, nicotine acted via α7AchR to upregulate γ-aminobutyric acid (GABA) A Rα2 and induces Muc5ac expression and mucus production 37. This effect would explain the increased mucin staining and Muc5ac expression detected in mouse lungs following exposure to nicotine-containing e-cigarettes.…”

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case‐Control Study

“…Moreover, a number of nonneuronal cells, including T cells, macrophages, and airway epithelial cells, express nAChRs and may synthesize acetylcholine 27. Although not yet examined for gallbladder epithelium, in the airway nAChRs are expressed by epithelial cells28, 29 and nicotine has been demonstrated to decrease mucus transport,30 increase mucin expression and mucus secretion,31, 32 alter mucus hydration, and increase the viscosity of mucus 33. Nicotine also has been described to cause relaxation of guinea pig gallbladder by a mechanism independent of nAChRs 34.…”

Gestational Exposure of Mice to Secondhand Cigarette Smoke Causes Bronchopulmonary Dysplasia Blocked by the Nicotinic Receptor Antagonist Mecamylamine

“…SS contains many toxic chemicals, including nicotine, and nAChRs are present on many non-neuronal cell types, including endothelial (Cooke and Ghebremariam 2008) and lung epithelial cells (Gundavarapu et al 2012). Thus, it is possible that SS affects lung alveolarization, angiogenesis, and surfactant proteins through nAChRs.…”

“…For example, exposure of adult mice to CS/nicotine suppresses allergic responses (Mishra et al 2008), but prenatal exposure to SS strongly exacerbates allergen-induced atopy and T-helper 2 (Th2) cell polarization (Singh et al 2011). Similarly, unlike its anti-angiogenic effects during gestational period, nicotine stimulates neovascularization (Cooke and Ghebremariam 2008) and airways mucus formation (Gundavarapu et al 2012; Singh et al 2011). A potential explanation is that long-term exposure to low levels of CS/nicotine may promote desensitization or loss of nAChRs, and these receptors may be important in regulating lung growth.…”