Lung diseases are also a major public health problem. Chronic obstructive pulmonary disease (COPD) will be the third cause of mortality worldwide in 2020 and lung cancer is the leading cause of cancer-related mortality across the world with over 1.3 million deaths each year. Most of these diseases are related to smoking. Cigarette smoke contains 250 components considered as harmful and at least 55 carcinogens. The effects of nicotine and mutagenic nicotine metabolites such as N-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)1-butanone (NNK) are mediated by nicotinic acetylcholine receptors (nAChRs). These receptors are present in the airway epithelium and the understanding of their role in the physiopathology of lung diseases represents an important challenge for a better understanding of lung pathology. In normal conditions, the diversity of the epithelial cells lining the airways is particularly well adapted to the protection of the airway mucosa. This epithelium is permanently submitted to numerous aggressions, particularly cigarette smoke, which lead to repair processes. The airway repair may be controlled, with the restoration of a normal functional epithelium, but it may be deregulated in chronic inflammatory diseases such as COPD, with a remodelling of the epithelium leading to chronic lesions and favouring the genesis of pre-neoplastic lesions. At last, tumour invasion has been considered as an abnormal spatiotemporally uncontrolled repair of a transformed epithelium. In all these conditions, airway epithelial cells display a wide plasticity which conditions these normal, deregulated and uncontrolled repair processes. Thus, the study of the mechanisms and regulation of cell plasticity of airway epithelial cells will allow to better understand how an airway epithelium maintains its integrity, how this airway epithelium is remodelled, and how transformed airway epithelial cells become invasive.
In previous studies, we have demonstrated in a collaboration the presence of nAChRs in the airway epithelium and their implication in the migration of bronchial cells during the wound repair of the epithelium for a3a5b2 nAChR, and in the differentiation of the bronchial epithelium in regeneration processes for the a7 nAChR. Moreover, three independent consortia published their findings on Whole Genome Association Studies (WGAS) implicating a locus on human chromosome 15q25 in the susceptibility to lung cancer. The study by Hung et al. showed that this susceptibility is not dependent on smoking behaviour, and they did identify polymorphisms also in non-smokers. This locus, as above, encompasses three genes for nAChR subunits, the subunits coding for a3, a5, and b4, also designated CHRNA3, CHRNA5 and CHRNB4, respectively. These three studies were the first to implicate nAChR genes in the susceptibility to lung cancer, but the role of these polymorphisms in the physiology and the physiopathology of the airway epithelium remains undetermined. The aim of our current approach is to dissect, in mouse models and human lung tissues, the implication of these different nicotinic subunits and their polymorphisms in the plasticity of the airway epithelium from normal conditions to the epithelial remodelling as it is observed in COPD, leading to preneoplastic lesions, and to tumour progression.