A chromosome 2 locus influences the onset of radiation-induced lung disease in mice.

Purpose: The onset of distress from radiation-induced lung disease differs among patients and among inbred strains of mice exposed to thoracic cavity radiotherapy. For the latter specifically, C3H/HeJ mice present distress due to pneumonitis at approximately 10-14 weeks following thoracic irradiation, while C57BL/6J mice show distress due to pneumonitis with pulmonary fibrosis at 22-30 weeks. Mapping studies completed in offspring derived from these inbred strains revealed a chromosome 2 locus to be linked to onset of distress in irradiated mice. Herein, we bred and phenotyped a panel of chromosome 2 subcongenic mice with 64 Mb of C3H/HeJ alleles on a C57BL/6J background, to investigate the contribution of the chromosome 2 locus to radiation-induced lung disease.

Materials and methods: Mice received 18 Gy to the thoracic cavity and were monitored for the onset of distress. Lung disease was assessed histologically and with bronchoalveolar lavage.

Results: Following whole thorax irradiation, subcongenic mice with C3H/HeJ alleles from 95 to 123 Mb showed significantly earlier onset of respiratory distress (16-22 weeks; p < .02) from pneumonitis and fibrosis compared to C57BL/6J mice. These subcongenic mice did not differ from C57BL/6J mice in pneumonitis (p = .23), mast cell counts (p = .96), or lavage neutrophils (p = .69), evident at distress. In silico analyses reveal 246 protein coding genes mapped within the reduced region, 52 of which differ in pulmonary expression of C3H/HeJ, compared to C57BL/6J, mice after whole thorax irradiation.

Conclusions: We have identified a 28 Mb region of chromosome 2 to influence the onset of radiation-induced lung disease in mice.