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 ,: hypothesized that individual variation in susceptibility to radiati on-induced pulmonary fibrosis is genetically controlled, A genetic mod el has been developed from the fibrosis-prone C57BL/6J and the fibrosi s-resistant C3Hf/Kam mouse strains, Inheritance of the fibrotic phenot ype was characterized in F1 and Fs (F1 intercross) generations derived from the parental strains, Genetic mapping was used to determine whet her the quantitative trait loci (QTL), which influence susceptibility to bleomycin-induced lung fibrosis in these progenitor strains, could be implicated in susceptibility to radiation-induced lung fibrosis. Mi ce were treated with PLL. or 16 Gy (Co-60) to the whole thorax, The do ses were selected to investigate the response at the LD50 and LD100 of C3Hf/Kam mice, The animals were sacrificed 33 weeks after treatment o r when moribund, The percentage of lung with fibrosis for each mouse w as quantified with image analysis of a histological section of the lun g, For both the II-and 16-Gy data sets, heritability was estimated at 38 +/- 11%, and the number of genetic factors influencing susceptibili ty to pulmonary fibrosis was estimated to be one or two, Two hundred f ifty-five F2 intercross mice were genotyped with markers at the bleomy cin loci on chromosomes II and 17 (chromosome 17 markers at the major histocompatibility complex), Genetic linkage was established for the m arker on chromosome 17 (P = 3.0 x 10(-6)), which accounts for 6.6% of the FZ phenotypic variance but not for the markers surrounding the QTL on chromosome 11 (P = 0.37). The inheritance data suggested that susc eptibility to radiation-induced pulmonary fibrosis is a heritable trai t controlled by tyro genetic loci, and through genomic mapping,,a QTL on chromosome 17 was identified as one of the loci.