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

Ming Zhang, Jun Qian, Xianying Xing, Feng Ming Kong, Lujun Zhao, Ming Chen, Theodore S. Lawrence

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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-α (TNF-α) pathway as a novel radioprotection strategy. Experimental Design: Mouse lungs were irradiated with various doses and assessed at varying times for TNF-α production. Lung toxicity was measured by apoptosis and pulmonary function testing. TNF receptor1 (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-α by macrophages in BALB/cmice 3 to 24 hours after radiation (15 Gy). A similar maximal induction was found 1week 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-α production correlates with early cell apoptosis and latent lung function damage. Inhibition of lung TNFR1is selectively radioprotective for the lung without compromising tumor response. These findings support the development of a novel radioprotection strategy using inhibition of the TNF-α pathway.

Original languageEnglish (US)
Pages (from-to)1868-1876
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number6
DOIs
StatePublished - Mar 15 2008

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zhang, M., Qian, J., Xing, X., Kong, F. M., Zhao, L., Chen, M., & Lawrence, T. S. (2008). Inhibition of the tumor necrosis factor-α pathway is radioprotective for the lung. Clinical Cancer Research, 14(6), 1868-1876. https://doi.org/10.1158/1078-0432.CCR-07-1894