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Etude des mécanismes moléculaires responsables d'un état inflammatoire intrinsèque dans la mucoviscidose.

Summary:
While multiple organs are affected in cystic fibrosis (CF) patients, chronic lung disease is the most severe clinical manifestation caused by chronic bacterial infection and concomitant airway inflammation. The sequence of events at the onset of pulmonary infection and inflammation is controversial and not fully characterized. The aim of this work was to highlight an early inflammatory state in CF airways before any infection and to investigate the molecular mechanisms underlying this intrinsic inflammation. We showed increased levels of pro-inflammatory proteins in the lungs of a CF fetus compared to the lungs of two normal fetuses. Using different CF cell models, we confirmed the over-production of numerous pro-inflammatory molecules. We then demonstrated that the transcription of these inflammatory genes is NF-kB and AP-1-dependent and that these transcription factors are activated through IKK and ERK kinase activation. We also identified that the IL-1b and bFGF inhibition, two pro-inflammatory proteins over-expressed in our CF models, decreased the expression of several pro-inflammatory genes. Among the molecules over-secreted by CF epithelial cells, chemokines such as IL-8, Gro-a, Gro-b, Gro-g and ENA-78 or growth factors such as VEGF and bFGF are know to be pro-angiogenic factors. We further demonstrated that conditioned media from CF epithelial cells were able to induce proliferation, migration and sprouting of cultured primary endothelial cells. Our data demonstrated that the absence of CFTR (CF transmembrane conductance regulator) at the plasma membrane leads to an intrinsic AP-1 and NF-kB activation. These activations lead to a pro-inflammatory state sustained through autocrine factor secretion and also through the angiogenic process induced by CF epithelial cells.

Identiferoai:union.ndltd.org:BICfB/oai:ETDULg:ULgetd-05312007-094239
Date21 June 2007
CreatorsVerhaeghe, Catherine
ContributorsChanson, M., Louis, R., Bureau, F., Bours, V., Peers, B., Beyaert, R., Piette, J., Oury, C.
PublisherUniversite de Liege
Source SetsBibliothèque interuniversitaire de la Communauté française de Belgique
Detected LanguageEnglish
Typetext
Formatapplication/pdf
Sourcehttp://bictel.ulg.ac.be/ETD-db/collection/available/ULgetd-05312007-094239/
Rightsunrestricted, Je certifie avoir complété et signé le contrat BICTEL/e remis par le gestionnaire facultaire.

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