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J Natl Cancer Inst. 2013 Oct 2;105(19):1474-84. doi: 10.1093/jnci/djt212. Epub 2013 Sep 19.

Role of type II pneumocyte senescence in radiation-induced lung fibrosis.

Author information

1
Affiliations of authors: Radiation Oncology Branch (DEC, US, JAH, WS, SZ, HA, AY, EJC) and Radiation Biology Branch (AS, AT), Center for Cancer Research, National Institutes of Health, Bethesda, MD.

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.

Comment in

PMID:
24052614
PMCID:
PMC3787909
DOI:
10.1093/jnci/djt212
[Indexed for MEDLINE]
Free PMC Article

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