Inhibition of the tumor necrosis factor-alpha pathway is radioprotective for the lung

Clin Cancer Res. 2008 Mar 15;14(6):1868-76. doi: 10.1158/1078-0432.CCR-07-1894.

Abstract

Purpose: Radiation-induced lung toxicity limits the delivery of high-dose radiation to thoracic tumors. Here, we investigated the potential of inhibiting the tumor necrosis factor-alpha (TNF-alpha) pathway as a novel radioprotection strategy.

Experimental design: Mouse lungs were irradiated with various doses and assessed at varying times for TNF-alpha production. Lung toxicity was measured by apoptosis and pulmonary function testing. TNF receptor 1 (TNFR1) inhibition, achieved by genetic knockout or antisense oligonucleotide (ASO) silencing, was tested for selective lung protection in a mouse lung metastasis model of colon cancer.

Results: Lung radiation induced local production of TNF-alpha by macrophages in BALB/c mice 3 to 24 hours after radiation (15 Gy). A similar maximal induction was found 1 week after the start of radiation when 15 Gy was divided into five daily fractions. Cell apoptosis in the lung, measured by terminal deoxyribonucleotide transferase-mediated nick-end labeling staining (mostly epithelial cells) and Western blot for caspase-3, was induced by radiation in a dose- and time-dependent manner. Specific ASO inhibited lung TNFR1 expression and reduced radiation-induced apoptosis. Radiation decreased lung function in BALB/c and C57BL mice 4 to 8 weeks after completion of fractionated radiation (40 Gy). Inhibition of TNFR1 by genetic deficiency (C57BL mice) or therapeutic silencing with ASO (BALB/c mice) tended to preserve lung function without compromising lung tumor sensitivity to radiation.

Conclusion: Radiation-induced lung TNF-alpha production correlates with early cell apoptosis and latent lung function damage. Inhibition of lung TNFR1 is selectively radioprotective for the lung without compromising tumor response. These findings support the development of a novel radioprotection strategy using inhibition of the TNF-alpha pathway.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / radiation effects
  • Lung / drug effects*
  • Lung / pathology
  • Lung / radiation effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oligonucleotides, Antisense / pharmacology*
  • Oligonucleotides, Antisense / therapeutic use
  • Radiation Pneumonitis / genetics
  • Radiation Pneumonitis / metabolism
  • Radiation Pneumonitis / pathology
  • Radiation Pneumonitis / prevention & control*
  • Radiation-Protective Agents / pharmacology*
  • Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Oligonucleotides, Antisense
  • Radiation-Protective Agents
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha