Abstract
Background Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood. Methods C57Bl/6NCr mice were exposed to thoracic irradiation (n = 3 per dose and time point for tissue collection). Microarray analysis of gene expression from irradiated murine lung was performed using one-way analysis of variance with post hoc Scheffe analysis. Senescence and type II airway epithelial cell (AECII) count were assayed in irradiated murine lung tissue (n = 3 per condition). Irradiated mice were treated with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), and fibrosis was assessed by collagen assays. All statistical tests were two-tailed. Results Gene expression in lung tissue from mice irradiated to 17.5 Gy clustered with that of aged unirradiated mice. Only fibrogenic exposures led to AECII senescence (0 Gy: 0.66% +/- 0.67%; 5 Gy: 4.5% +/- 1.19%; 17.5 Gy: 18.7% +/- 3.05; P = .007) and depletion (0 Gy: 2.89 per alveolus +/- 0.26; 5 Gy: 2.41 +/- 0.19; 17.5 Gy: 1.6 +/- 0.14; P < -001) at 30 weeks. Treatment of irradiated mice with DPI for 16 weeks markedly reduced collagen accumulation (5 ×6 Gy: 57.26 μg/lung +/- 9.91; 5×6 Gy +/- DPI: 36.54μg/lung +/- 4.39; P = .03) and AECII senescence (5×6 Gy: 37.61% +/- 4.82%; 5×6 Gy +/- DPI: 12.38% +/- 2.78; P < .001). Conclusions These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.
Original language | English |
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Pages (from-to) | 1474-1484 |
Number of pages | 11 |
Journal | Journal of the National Cancer Institute |
Volume | 105 |
Issue number | 19 |
DOIs | |
Publication status | Published - Oct 2 2013 |
Externally published | Yes |
ASJC Scopus subject areas
- Oncology
- Cancer Research