Genetic variation in the proliferation of murine pulmonary type II cells: basal rates and alterations following urethan treatment.

Susceptibility to urethan-induced pulmonary tumorigenesis varies among inbred strains of mice. A genetic basis for this variation was sought using three strains with widely differing tumor multiplicities after urethan treatment. Twenty-one mice from each of strains A/J (high susceptibility), BALB/cByJ (intermediate susceptibility; hereafter called cBy), and C57BL/6J (low susceptibility; hereafter called B6) were treated i.p. with 1 mg urethan/g body weight, and sacrificed at 0 (no urethan), 12, 24, 36, 48, 65, and 80 days after treatment (three mice per strain per time point). Each mouse was given 1 muCi [3H]thymidine/g body weight 45 min before sacrifice. Lungs were processed for autoradiography, and labeling indices were independently determined for non-tumor-associated type II cells and for tumor cells (most tumors arise from alveolar type II pneumocytes in A/J mice). Three categories of proliferative differences were found. First, statistically significant differences (P less than 0.05) among all strains were found for type II cell labeling indices in untreated mice, and these differences persisted for 65 days after urethan treatment. Proliferative rates were highest in A/J mice and lowest in B6 mice, while cBy mice were intermediate. Secondly, the peak of type II cell labeling occurred 12 days following urethan in strains A/J and cBy, but at 24 days in B6 mice. This difference is consistent with the fact that tumors were observed earlier following urethan treatment in A/J and cBy mice (at 36 days) than in B6 mice (at 48 days). Finally, the labeling indices in A/J and B6 tumors were high at first (6 and 4%) and then declined to 1-1.5% by 80 days after urethan treatment, while cBy tumor labeling indices remained at about 1.5% throughout the experimental period. These results suggest that the variation in susceptibility to urethan-induced lung tumorigenesis among different strains of mice is related to the normal basal rates of lung mitoses in these strains. Mice may be particularly sensitive to urethan during cell division, making strains with a higher rate of mitosis more susceptible to tumorigenesis.