Abstract
Differences in the pathogenesis of radiation-induced lung injury among murine strains offer a unique opportunity to elucidate the molecular mechanisms driving the divergence in tissue response from repair and recovery to organ failure. Here, we utilized two well-characterized murine models of radiation pneumonitis/fibrosis to compare and contrast differential gene expression in lungs 24 hours after exposure to a single dose of whole thorax lung irradiation sufficient to cause minor to major morbidity/mortality. Expression of 805 genes was altered as a general response to radiation; 42 genes were identified whose expression corresponded to the threshold for lethality. Three genes were discovered whose expression was altered within the lethal, but not the sublethal, dose range. Time-course analysis of the protein product of the most promising gene, resistin-like molecule alpha, demonstrated a significant difference in expression between radiosensitive versus radiotolerant strains, suggesting a unique role for this protein in acute lung injury.
Highlights
Differences in the pathogenesis of radiation-induced lung injury among murine strains offer a unique opportunity to elucidate the molecular mechanisms driving the divergence in tissue response from repair and recovery to organ failure
Over the past several years, we systematically characterized the pulmonary response to radiation among three genetically different, but related murine strains to select the most appropriate animal models to reflect the pathogenesis of radiation-induced lung disease (RILD) in humans and interrogate the underlying mechanisms of injury to improve target identification and test potential radiation injury mitigators for clinical translation[6,7,8,9]
In C57L/J mice irradiated at 10–12 weeks of age, the incidence of lethal pneumonitis/fibrosis increases sharply over a range of 9.0 to 12.0 Gy whole thorax lung irradiation (WTLI), with no significant difference observed between female versus male mice in 180-day survival (p = 0.13, Logistic Regression) (Fig. 1A)
Summary
Differences in the pathogenesis of radiation-induced lung injury among murine strains offer a unique opportunity to elucidate the molecular mechanisms driving the divergence in tissue response from repair and recovery to organ failure. Over the past several years, we systematically characterized the pulmonary response to radiation among three genetically different, but related murine strains to select the most appropriate animal models to reflect the pathogenesis of radiation-induced lung disease (RILD) in humans and interrogate the underlying mechanisms of injury to improve target identification and test potential radiation injury mitigators for clinical translation[6,7,8,9]. In those studies, we defined the dose-response, latency, duration, and pathogenesis of injury in age- and sex-matched C57L/J, CBA/J, and C57BL/6J mice. Expression of the most promising candidate gene, Retnla, was validated at serial time points after whole thorax lung irradiation (WTLI), covering the asymptomatic (1 day through 6 weeks) and symptomatic (to 180 days) phase in our rodent models and correlated with airway epithelial damage and inflammation
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