Positional Cloning Reveals Strain-Dependent Expression of Trim16 to Alter Susceptibility to Bleomycin-Induced Pulmonary Fibrosis in Mice

Pulmonary fibrosis is a disease of significant morbidity,with no effective therapeutics and an as yet incompletely defined genetic basis. the chemotherapeutic agent bleomycin induces pulmonary fibrosis in susceptible c57bl/6j mice but not in mice of the c3h/hej strain,and this differential strain response has been used in prior studies to map bleomycin-induced pulmonary fibrosis susceptibility loci named blmpf1 and blmpf2. in this study we isolated the quantitative trait gene underlying blmpf2 initially by histologically phenotyping the bleomycin-induced lung disease of sublines of congenic mice to reduce the linkage region to 13 genes. of these genes,trim16 was identified to have strain-dependent expression in the lung,which we determined was due to sequence variation in the promoter. over-expression of trim16 by plasmid injection increased pulmonary fibrosis,and bronchoalveolar lavage levels of both interleukin 12/23-p40 and neutrophils,in bleomycin treated b6.c3h-blmpf2 subcongenic mice compared to subcongenic mice treated with bleomycin only,which follows the c57bl/6j versus c3h/hej strain difference in these traits. in summary we demonstrate that genetic variation in trim16 leads to its strain-dependent expression,which alters susceptibility to bleomycin-induced pulmonary fibrosis in mice. © 2013 stefanov et al.