Gene expression profiles among murine strains segregate with distinct differences in the progression of radiation-induced lung disease

Molecular mechanisms underlying development of acute pneumonitis and/or late fibrosis following thoracic irradiation remain poorly understood. Here, we hypothesize that heterogeneity in disease progression and phenotypic expression of radiation-induced lung disease (RILD) across murine strains presents an opportunity to better elucidate mechanisms driving tissue response toward pneumonitis and/or fibrosis. Distinct differences in disease progression were observed in age-and sex-matched CBA/J, C57L/J and C57BL/6J mice over 1 year after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 hpost-exposure demonstrated> 5000genestobedifferentially expressed (P< 0.01; > twofold change) between strainswith early versus late onset of disease. An immediate divergence in early tissue response between radiation-sensitive and -resistant strains was observed. In pneumonitis-prone C57L/J mice, differentially expressed genes were enriched in proinflammatory pathways, whereas in fibrosis-prone C57BL/6J mice, genes were enriched in pathways involved in purine and pyrimidine synthesis, DNAreplication and cell division. At 24 h postWTLI, different patterns of cellular damage were observed at the ultrastructural level among strains butmicroscopic damage was not yet evident under light microscopy. These data point toward a fundamental difference in patterns of early pulmonary tissue response to WTLI, consistent with themacroscopic expression of injurymanifesting weeks to months after exposure. Understanding the mechanisms underlying development ofRILDmight lead tomore rational selection of therapeutic interventions to mitigate healthy tissue damage.