Murine susceptibility to radiation-induced pulmonary fibrosis is influenced by a genetic factor implicated in susceptibility to bleomycin- induced pulmonary fibrosis

From evidence of interpatient variability in normal tissue sensitivity to radiotherapy and from radiation studies using inbred mouse strains, it is hypothesized that individual variation in susceptibility to radiation- induced pulmonary fibrosis is genetically controlled. A genetic model has been developed from the fibrosis-prone C57BL/6J and the fibrosis-resistant C3Hf/Kam mouse strains. Inheritance of the fibrotic phenotype was characterized in F1 and F2 (F1 intercross) generations derived from the parental strains. Genetic mapping was used to determine whether the quantitative trait loci (QTL), which influence susceptibility to bleomcyin- induced lung fibrosis in these progenitor strains, could be implicated in susceptibility to radiation-induced lung fibrosis. Mice were treated with 14 or 16 Gy (⁶⁰Co) to the whole thorax. The doses were selected to investigate the response at the LD₅₀ ad LD₁₀₀ of C3Hf/Kam mice. The animals were sacrificed 33 weeks after treatment or when moribund. The percentage of lung with fibrosis for each mouse was quantified with image analysis of a histological section of the lung. For both the 14- and 16-Gy data sets, heritability was estimated at 38 ± 11%, and the number of genetic factors influencing susceptibility to pulmonary fibrosis was estimated to be one or two. Two hundred fifty-five F2 intercross mice were genotyped with markers at the bleomycin loci on chromosomes 11 and 17 (chromosomes 17 markers is at the major histocompatibility complex). Genetic linkage was established for the marker on chromosome 17 (P = 3.0 x 10^-6), which accounts for 6.6% of the F2 phenotypic variance but not for the markers surrounding the QTL on chromosome 11 (P = 0.37). The inheritance data suggested that susceptibility to radiation-induced pulmonary fibrosis is a heritable trait controlled by two genetic loci, and through genomic mapping, a QTL on chromosome 17 was identified as one of the loci.