title: Gene expression profiles among murine strains segregate with distinct differences in the progression of radiation-induced lung disease.
abstract: 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 h post-exposure demonstrated >5000 genes to be differentially expressed (P<0.01; >twofold 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 manifesting weeks to months after exposure. Understanding the mechanisms underlying development of RILD might lead to more rational selection of therapeutic interventions to mitigate healthy tissue damage.
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA ijackson@som.umaryland.edu.
authors.forename: Isabel L
authors.identifier: 0000-0003-2998-7606
authors.initials: IL
authors.lastname: Jackson
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
authors.forename: Fitsum
authors.initials: F
authors.lastname: Baye
authors.affiliation: Thomas Jefferson University Hospital, Molecular and Genomic Pathology Lab, Philadelphia, PA 19107, USA.
authors.forename: Chirayu P
authors.initials: CP
authors.lastname: Goswami
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202, USA.
authors.forename: Barry P
authors.initials: BP
authors.lastname: Katz
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Zodda
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Radmila
authors.initials: R
authors.lastname: Pavlovic
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Ganga
authors.initials: G
authors.lastname: Gurung
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Winans
authors.affiliation: Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21202, USA.
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D004307:Dose-Response Relationship, Radiation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053208:Kaplan-Meier Estimate; D008168:Lung / Q000473:pathology / Q000528:radiation effects; D008171:Lung Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011832:Radiation Injuries / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D060888:Real-Time Polymerase Chain Reaction; D012307:Risk Factors; D013909:Thorax / Q000473:pathology / Q000528:radiation effects
chemical_list: D000209:Acute-Phase Proteins; D012333:RNA, Messenger
keywords: Gene expression profiling; Lung fibrosis; Murine strain differences; Radiation pneumonitis