α7 Nicotinic Acetylcholine Receptor Regulates Airway Epithelium Differentiation by Controlling Basal Cell Proliferation

Abstract

Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the ␣7 nicotinic acetylcholine receptor (nAChR), which is highly permeable to Ca 2؉ , is involved in lung morphogenesis. Here, we have investigated the potential role of the ␣7 nAChR in the regulation of airway epithelial basal cell proliferation and the differentiation of the human airway epithelium. In vivo during fetal development and in vitro during the regeneration of the human airway epithelium, ␣7 nAChR expression coincides with epithelium differentiation. Inactivating ␣7 nAChR function in vitro increases cell proliferation during the initial steps of the epithelium regeneration, leading to epithelial alterations such as basal cell hyperplasia and squamous metaplasia, remodeling observed in many bronchopulmonary diseases. The regeneration of the airway epithelium after injury in ␣7 The respiratory epithelium, which is constantly exposed to airborne pollutants, is frequently injured, which results in altered epithelial functions. To restore these functions, the respiratory epithelium must undergo rapid repair via epithelial cell spreading and migration and regenerate its structure via basal cell proliferation and differentiation.

Control of Lung Epithelial Growth by a Nicotinic Acetylcholine Receptor

“…However, the airways of uninjured ␣7 nAChR-deficient mice also had significant areas with disrupted morphology and basal cell hyperplasia. 4 Nevertheless, the data presented are consistent with the work of others showing that ␣7 nAChR-deficient mice are sensitive to acute lung injury and have deficiencies in fluid clearance mediated by alveolar epithelium. 6 In this study, acute nicotine treatment facilitated recovery from acute lung injury; however, whether chronic low-dose nicotine administration would have a deleterious effect was not tested.…”

“…Specifically, the authors found that the injury response in airways of ␣7 nAChR-deficient mice was characterized by significant basal cell hyperplasia compared with wild-type mice. 4 Treatment of cultured human airway cells or ex vivo human lung explants with ␣-bungarotoxin, a neurotoxin capable of blocking ␣7 nAChR function, had a similar effect on the injury response. As a direct demonstration that ␣7 nAChR expression controls proliferation in cultured cells, a human lung basal epithelial cell line transfected with either small interfering RNA or cDNA (to deplete or enhance ␣7 nAChR expression) showed an inverse correlation between the level of ␣7 nAChR expression and the Supported by the Emory Alcohol and Lung Biology Center (National Institutes of Health [NIH] grant P50-AA013757 to J.R. and M.K.…”

“…Intriguingly, the airways of lungs isolated from heavy smokers showed areas with significant basal cell hyperplasia, which were morphologically similar to the injury models in which ␣7 nAChR expression or function was inhibited. 4 Because nicotine exposure would normally be expected to activate ␣7 nAChRs, one way to reconcile these apparently discordant results is to consider that smokers' lungs are exposed to a long-term low dose of nicotine, which could desensitize ␣7 activity, 11,12 and thus physiologically mimic ␣7 nAChR-deficient mice.…”

“…Defining signaling pathways controlled by ␣7 nAChR that are linked to differentiation would strengthen this case, but these studies await further exploration. Potential ␣7 nAChR regulatory candidates include the Foxj1, 4 the wnt/␤-catenin axis, 18,19 and the peroxisome proliferator-activated receptors. 20 Furthermore, it will be interesting to examine whether the effects on epithelial cells noted by Maouche et al are shared by other cells, because ␣7 nAChRs are expressed in a wide array of lung cells including endothelial cells, fibroblasts, alveolar epithelial cells, and macrophages.…”

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.…”