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Implication des microARN dans le développement des maladies pulmonaires à composante environnementale : exemple de le fibrose pulmonaire idiopathique

Abstract : MicroRNAs are small non-coding RNAs with about 20 nucleotides that regulate gene expression by binding to the 3' UTR end of target mRNAs, thus allowing their degradation or stopping their translation into proteins. To date, many studies have shown the involvement of microRNAs in various physiological or pathological processes; their role in the body's response to environmental toxic substances is beginning to be mentioned. It is characterized by the presence of fibroblast/myofibroblast proliferation foci responsible for excessive extracellular matrix production, progressive and irreversible destruction of lung architecture leading to loss of respiratory function. The repeated aggression of the respiratory epithelium by environmental (or xenobiotic) chemicals is strongly suspected in the initiation of IVF. The first objective of my research was to identify microRNAs that may be involved in the pathogenesis of idiopathic pulmonary fibrosis (IVF) and to specify the function(s) of these microRNAs of interest. To achieve this objective, we studied two microRNAs, miR-199a-5p and miR-214-3p, which had the particularity of being significantly overexpressed in the lungs of mice with pulmonary fibrosis. Systematic analysis of the expression profiles of fibroblast genes overexpressing miR-199a-5p and miR-214-3p allowed us to identify a large number of genes that were significantly modulated by these two microRNAs. We were able to establish the respective involvement of miR-199a-5p and miR-214-3p in the regulation of the profibrotic pathway TGFβ and in Fas-ligand mediated apoptosis of pulmonary fibroblasts. The second objective of my research was to identify the in vitro cellular model closest to lung tissue in order to study the impact of environmental toxic compounds on the pathogenesis of respiratory diseases and, in particular, of IVF. To do this, we compared the gene expression profiles of all proteins involved in the metabolism and elimination of xenobiotics, 10 cell lines and 4 primary cultures of human bronchial epithelial cells, with those previously observed by our team in human bronchopulmonary tissues. Exposure of the most relevant cellular model to air pollutants will identify the microRNAs associated with the pulmonary toxicity of these chemical compounds and verify whether these microRNAs regulate signaling pathways common to those involved in the pathogenesis of IVF.
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Elisabeth Ngoubo Ngangue-Courcot. Implication des microARN dans le développement des maladies pulmonaires à composante environnementale : exemple de le fibrose pulmonaire idiopathique. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2012. Français. ⟨NNT : 2012LIL2S051⟩. ⟨tel-01927224⟩

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