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

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. 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. 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; <i>p</i> &lt; .02) from pneumonitis and fibrosis compared to C57BL/6J mice. These subcongenic mice did not differ from C57BL/6J mice in pneumonitis (<i>p</i> = .23), mast cell counts (<i>p</i> = .96), or lavage neutrophils (<i>p</i> = .69), evident at distress. <i>In silico</i> 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. We have identified a 28 Mb region of chromosome 2 to influence the onset of radiation-induced lung disease in mice.