Abstract
Susceptibility to fibrotic lung disease differs among people and among inbred strains of mice exposed to bleomycin where C57BL/6J mice are susceptible and C3H/HeJ mice are spared fibrotic disease. Genetic mapping studies completed in offspring derived from these inbred strains revealed the inheritance of C57BL/6J alleles at loci, including the major locus on chromosome 17, called Blmpf1 bleomycin-induced pulmonary fibrosis 1, to be linked to pulmonary fibrosis in treated mice. In the present study, to reduce the interval of Blmpf1, we bred and phenotyped a panel of subcongenic mice with C3H/HeJ alleles in a C57BL/6J background. Subcongenic mice received bleomycin via osmotic minipump and the fibrosis phenotype was measured histologically. Inheritance of C3H/HeJ alleles from 34.31 to 35.02 Mb was revealed to spare bleomycin-induced pulmonary fibrosis of C57BL/6J mice. From database analysis, 40 protein coding genes have been mapped to this reduced Blmpf1 interval, 18 of which contain C57BL/6J:C3H/HeJ sequence polymorphisms predicted to affect protein structure or to confer allele-dependent expression, and by RT-PCR analysis of lung tissue, we show 6 of these genes to differ in expression between C57BL/6J and C3H/HeJ mice. Genes known to regulate T cell numbers and activation (Btnl family, Notch4) are among the limited list of potential causal variants leading to lung disease in this model and the bronchoalveolar lavage of protected subcongenic mice had fewer lymphocytes, post bleomycin, than did C57BL/6J mice. We conclude that Blmpf1genes contributing to the susceptibility to bleomycin-induced pulmonary fibrosis could alter the adaptive immune response of C57BL/6J mice.
Highlights
Pulmonary fibrosis is a genetically complex disease which can result from known environmental or therapeutic exposures, or can occur idiopathically (Lederer and Martinez 2018)
Mice of subcongenic line 1 contain the minimal C3H donor region, among evaluated subcongenic lines, and these mice were protected from bleomycin-induced pulmonary fibrosis, (P = 2.2 × 10− 4 vs. C57BL/6J mice) indicating that at least one Blmpf quantitative trait locus maps to this region
We have reduced the genomic region linked to susceptibility to a clear and clinically relevant pulmonary fibrosis phenotype to 0.71 Mb
Summary
Pulmonary fibrosis is a genetically complex disease which can result from known environmental or therapeutic exposures, or can occur idiopathically (Lederer and Martinez 2018). The lung phenotype of C57BL/6J mice, following a 7-day subcutaneous dose of bleomycin, consists of an alveolar inflammatory cell infiltrate with subpleural regions of fibrosis; a pathology that has been described for clinical cases of idiopathic pulmonary fibrosis (Gross and Hunninghake 2001; Lederer and Martinez 2018; Nuovo et al 2012). T lymphocytes have been pathologically implicated in fibrosis in this model as antibody depletion of CD3+ cells has been shown to abrogate the development of the disease (Huaux et al 2003; Sharma et al 1996), while T regulatory cell expansion exacerbates fibrosis (Birjandi et al 2016)
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