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Role of type II pneumocyte senescence in radiation-induced lung fibrosis.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2013 Oct 02; Vol. 105 (19), pp. 1474-84. Date of Electronic Publication: 2013 Sep 19. - Publication Year :
- 2013
-
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.<br />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.<br />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).<br />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.
- Subjects :
- Animals
Disease Models, Animal
Dose-Response Relationship, Radiation
Gene Expression Regulation radiation effects
Lung pathology
Lung radiation effects
Mice
Mice, Inbred C57BL
NADPH Oxidases antagonists & inhibitors
Onium Compounds
Time Factors
Tissue Array Analysis
Alveolar Epithelial Cells pathology
Alveolar Epithelial Cells radiation effects
Cellular Senescence radiation effects
Collagen metabolism
NADPH Oxidases metabolism
Pulmonary Fibrosis etiology
Pulmonary Fibrosis pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2105
- Volume :
- 105
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 24052614
- Full Text :
- https://doi.org/10.1093/jnci/djt212