Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse

Based on the range of patient responses to treatment, and on animal studies, it is hypothesized that individual variation in sensitivity to bleomycin-induced pulmonary fibrosis is controlled genetically. A genetic model has been developed by (a) establishing a distinct difference in bleomycin-induced lung damage in two inbred strains of mice [parental generation: C57BL/6J (fibrosis-prone phenotype) and C3Hf/Kam (fibrosis-resistant phenotype)] and (b) characterizing inheritance of the fibrosing phenotype in the F1 (first filial) and F2 (F1 intercross; second filial) generations derived from the parental strains. Male mice received 100 mg/kg and female mice 125 mg/kg of bleomycin via s.c. osmotic minipump. The animals were sacrificed 8 weeks after treatment or when their breathing rate indicated respiratory distress. The percentage of lung with fibrosis for each mouse was quantified with image analysis of a histological section of the left lung. The mean percentage of fibrosis for the C57BL/6J males was 8.4 +/- 0.8% (SE) and 4.4 +/- 0.8% for females, and the C3Hf/Kam mice of either sex did not present the fibrosing lesion (mean score, 0%). Significant difference (P = 6 x 10(-6)) was measured in percentage of fibrosis between the two strains of F1 males, but not F1 females (P = 0.38), suggesting the presence of an X-linked factor associated with the fibrosing phenotype. From an ANOVA the X-linked factor is estimated to contribute 19% of the fibrosis phenotype. A genetic model of two or three loci controlling the fibrosing phenotype is proposed from the data of the parental, F1, and F2 generations. The mouse model demonstrates that susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait controlled by a few genetic loci.