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

Deborah E. Citrin, Uma Shankavaram, Jason A. Horton, William Shield, Shuping Zhao, Hiroaki Asano, Ayla White, Anastasia Sowers, Angela Thetford, Eun Joo Chung

Research output: Contribution to journalArticlepeer-review

90 Citations (Scopus)

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 languageEnglish
Pages (from-to)1474-1484
Number of pages11
JournalJournal of the National Cancer Institute
Volume105
Issue number19
DOIs
Publication statusPublished - Oct 2 2013
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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