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.