Browsing by Author "Vujaskovic, Zeljko"

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    A preclinical rodent model of radiation-induced lung injury for medical countermeasure screening in accordance with the FDA animal rule
    (Wolters Kluwer, 2012) Jackson, Isabel L.; Xu, Puting; Hadley, Caroline; Katz, Barry P.; McGurk, Ross; Down, Julian D.; Vujaskovic, Zeljko; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    The purpose of pre-clinical murine model development is to establish that the pathophysiological outcome of our rodent model of radiation-induced lung injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation lung injury in humans. In this study, we assessed this issue by evaluating the relationship between morbidity (pulmonary function, histopathologic damage) and mortality among three strains of mice, C57BL/6J, CBA/J, and C57L/J. These different strains display variations in latency and phenotypic expression of radiation-induced lung damage. By comparing the response of each strain to the human pulmonary response, we established an appropriate animal model(s) of human radiation-induced pulmonary injury. Observations in the C57L/J and CBA/J murine models can be extrapolated to the human lung for evaluation of mechanisms of action of radiation as well as future efficacy testing and approving agents that fall under the “Animal Rule” of the US Food and Drug Administration (FDA) (21 CFR Parts 314 and 601).
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    Gene expression profiles among murine strains segregate with distinct differences in the progression of radiation-induced lung disease
    (The Company of Biologists, 2017-04-01) Jackson, Isabel L.; Baye, Fitsum; Goswami, Chirayu P.; Katz, Barry P.; Zodda, Andrew; Pavlovic, Radmila; Gurung, Ganga; Winans, Don; Vujaskovic, Zeljko; Biostatistics, School of Public Health
    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.