Identification of bleomycin and radiation-induced pulmonary fibrosis susceptibility genes in mice

Pulmonary fibrosis is a complex trait disease of cells and collagen deposition in the lung parenchyma with unknown genes influencing the susceptibility to the disease. Genetic study of pulmonary fibrosis could allow the identification of new susceptibility genes, which could lead to a better understanding of the disease. Treatments with a chemotherapeutic agent called bleomycin or with thoracic irradiation are known to induce pulmonary fibrosis in human and mice. We made use of the known susceptibility to develop bleomycin and radiation-induced pulmonary fibrosis of C57Bl/6J mice and of the known resistance of A/J and C3H/HeJ mice to identify susceptibility genes by evaluating several mouse crosses. In this thesis, we identified putative quantitative trait loci (QTL) on chromosome 1, 3, 5, 6, 9 and 12 for bleomycin-induced pulmonary fibrosis and markers associated with fibrosis development on chromosome 3 and 4 for radiation-induced pulmonary fibrosis in a panel of recombinant congenic (RC) strains derived from C57Bl/6J and A/J mice. Candidate genes for bleomycin-induced pulmonary fibrosis were then evaluated for chromosome 6 QTL and for the previously identified Blmpf1 QTL on chromosome 17. As several natural killer cells genes were located under the peak of chromosome 6 linkage region, natural killer deficient mice were treated with bleomycin and NK deficiency was found not to influence pulmonary fibrosis development. Several class I major histocompatibility complex (MHC) genes were located under the peak of Blmpf1 locus and the deficiency in MHC class I molecules of β2-microglobulin knock-out mice did not result in an altered lung phenotype, so NK cells genes and MHC class I genes were excluded as bleomycin-induced pulmonary fibrosis candidates. The size of Blmpf1 locus was then reduced to a 0.8 megabase region containing 45 genes by studying B6:A/J and MHC congenic mice. Complement component 4b (C4b) was a candidate gene in this new reduced region and was f%%%%La fibrose pulmonaire est une maladie causee par l'infiltration de cellules et de collagene dans le poumon. Ce trait complexe est influence par des genes inconnus et une etude genetique de la fibrose pulmonaire pourrait mener a l'identification de nouveaux genes de susceptibilite, ce qui pourrait ameliorer la comprehension de cette maladie. Les traitements de chimiotherapie avec de la bleomycine ou de radiotherapie peuvent entrainer le developpement de fibrose pulmonaire chez l'homme et la souris. Par exemple, certaines souches de souris sont susceptibles au developpement de la fibrose pulmonaire, telles que la lignee C57BL/6J, alors que les lignees A/J et C3H sont resistantes au developpement de cette maladie. Dans cette these, nous avons identifie plusieurs locus de caracteres quantitatifs (QTL) sur les chromosomes 1, 3, 5, 6, 9 et 12 dans le modele murin de fibrose pulmonaire causee par la bleomycine ainsi que des marqueurs associes avec le developpement de la fibrose pulmonaire causee par la radiation sur les chromosomes 3 et 4 en utilisant des lignees…