Title: 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. In this study distinct differences in disease progression were observed in ageand sex-matched CBA/J, C57L/J, and C57BL/6J mice over 1 y after graded doses of whole-thorax lung irradiation (WTLI). Separately, comparison of gene expression profiles in lung tissue 24 h postexposure demonstrated >5,000 genes to be differentially expressed (P < 0.01; >2-fold change) between strains with 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, DNA replication, and cell division. At 24 h post-WTLI, different patterns of cellular damage were observed at the ultrastructural level among strains but microscopic 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 the macroscopic expression of injury D is ea se M o de ls & M ec ha ni sm s • D M M • A dv an ce a rt ic le manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD may lead to more rational selection of therapeutic interventions to mitigate normal tissue damage.