Prenatal Nicotine Exposure Increases GABA Signaling and Mucin Expression in Airway Epithelium

Abstract

Maternal smoking during pregnancy increases the risk of respiratory disease in offspring, but surprisingly little is known about the underlying mechanisms. Nicotinic acetylcholine receptors (nAChRs) expressed in bronchial epithelial cells (BECs) mediate the effects of nicotine on lung development and function. Recently, BECs were also shown to express a GABAergic paracrine loop that was implicated in mucus overproduction in asthma. We therefore investigated the interactions between cholinergic and GABAergic signaling in rhesus macaque BECs, and found that nicotine upregulated GABA signaling in BECs through the sequential activation of BEC nAChR and GABA receptors. The incubation of primary cultures of rhesus BECs increased concentrations of GAD, GABA A receptors, and mucin mRNA. The nicotine-induced increase in glutamatic acid decarboxylase (GAD) and GABA A receptor mRNA resulted in increased GABAinduced currents and increased expression of mucin. The ability of nicotine to increase mucin expression was blocked by nicotinic and GABA A antagonists. These results implicate GABA signaling as a middleman in nicotine's effects on mucus overproduction. Similar effects of nicotine on GABA signaling and the expression of mucin were seen in vivo after chronic exposure of rhesus monkeys to nicotine. These data provide a new mechanism linking smoking with the increased mucin seen in asthma and chronic obstructive pulmonary disorder, and suggest a new paradigm of communication between non-neuronal transmitter systems in BECs. The existence of neural-like transmitter interactions in BECs suggests that some drugs active in the central nervous system may possess previously unexpected utility in respiratory diseases.

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.…”

Bronchial epithelium in children: a key player in asthma

“…For example, active maternal smoking during pregnancy has been shown to increase the risk of asthma and chronic obstructive pulmonary disease [29]. Indeed, the bronchial epithelium expresses nicotinic receptors and prenatal exposure to nicotine in vivo has been shown to upregulate mucin secretion in an in vitro model of macaque bronchial epithelium (newborn to 1 year old animals) [30].…”

Novel Therapies to Inhibit Mucus Synthesis and Secretion in Airway Hypersecretory Diseases

“…IL-13 regulates airway epithelium signalling via γ-aminobutyric acid (GABA): although it is the main inhibitory neurotransmitter in the central nervous system, its effects in the bronchial epithelium are actually excitatory and its signalling contributes to mucus overproduction [31]. This is due to intracellular chloride ion levels exceeding those in the airway lumen; opening of GABA channels results in Cl - efflux, making the cell membrane potential less negative and easier to excite [15,30].…”

“…IL-13 increases GABA expression in mouse airway epithelial cells in vivo [32]. Nicotine increases expression of GABA A receptors and nAChRs in rhesus macaque bronchial epithelial cells: nAChR activation increases signalling in GABAergic systems; therefore, nicotine-induced increased nAChR expression increases airway GABA A channel activity further [16,31]. …”

“…Importance of GABA in IL-13-induced inflammation and mucin production in asthma was highlighted in section 4.1.2, and GABA A receptor antagonists (bicuculline, picrotoxin) reduce mucin production in airway rhesus monkey epithelial cells [16,31]. However, non-selective GABA blockade is unlikely to be an appropriate therapy for asthma or COPD, since its inhibitory effects are too widespread in the body and its blockade would bring about detrimental or undesirable effects (such as convulsions, hypertension, and insomnia); many are due to brain overactivity.…”