Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure.

Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na(+) absorption, a defective cAMP-dependent Cl(-) conductance, higher concentrations of Na(+), Cl(-), K(+), and Ca(2+) in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca(2+) entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.

{alpha}7 nicotinic acetylcholine receptor regulates airway epithelium differentiation by controlling basal cell proliferation.

Airway epithelial basal cells are known to be critical for regenerating injured epithelium and maintaining tissue homeostasis. Recent evidence suggests that the alpha7 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 alpha7 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, alpha7 nAChR expression coincides with epithelium differentiation. Inactivating alpha7 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 alpha7(-/-) mice is delayed and characterized by a transient hyperplasia of basal cells. Moreover, 1-year-old alpha7(-/-) mice more frequently present basal cells hyperplasia. Modulating nAChR function or expression shows that only alpha7 nAChR, as opposed to heteropentameric alpha(x)beta(y) nAChRs, controls the proliferation of human airway epithelial basal cells. These findings suggest that alpha7 nAChR is a key regulator of the plasticity of the human airway epithelium by controlling basal cell proliferation and differentiation pathway and is involved in airway remodeling during bronchopulmonary diseases.

Role of nicotinic acetylcholine receptors in cell proliferation and tumour invasion in broncho-pulmonary carcinomas.

OBJECTIVES: Nicotine and its associated nicotinic acetylcholine receptors (nAChRs) are believed to be involved in the progression of lung carcinomas. This study aimed at examining the localization of nAChRs in human lung tumours and, by using primary cultures of tumour cells derived from these tumours, determining the nAChR roles in cell proliferation and tumour invasion. MATERIALS AND METHODS: Immunohistochemistry was used to assess nAChR expression in non-small cell lung carcinomas (NSCLC). Primary cultures of tumour cells were established from NSCLC tissue samples and the effects of nicotine and nAChR antagonists on cell proliferation and invasion were assessed. RESULTS: α5, α7, ß2 and ß4 nAChR subunits were expressed in all adenocarcinomas (AC) and squamous cell carcinomas (SCC) tissue samples. In AC, all subunits were identified in glandular structures. In SCC, α5, ß2 and ß4 subunits were essentially identified in tumour cells at invasive fronts, whereas α7 subunit was mainly present in the most differentiated tumour cells and less frequently at invasive fronts. In AC and SCC, there was an inverse distribution of cell proliferation marker Ki-67 and α7 nAChR. Both α7 nAChR and heteromeric nAChRs positively regulated in vitro tumour invasion in NSCLC. Heteromeric nAChRs had a limited activity in regulating tumour cell proliferation in vitro. In contrast, α7 nAChR was a repressor of proliferation in tumour cells isolated from well differentiated NSCLC but mediated the pro-proliferative activity of nicotine in cells isolated from poorly differentiated NSCLC. CONCLUSION: α7 nAChR and heteromeric α5*ß2*ß4* nAChRs play a role in ex vivo tumour progression by stimulating invasion and, depending on the differentiation status of the tumour, by regulating proliferation. Our results suggest that the use of α7 nAChR antagonists to prevent lung cancer progression should be restricted to poorly differentiated tumours.