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


METHODS
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.


CONCLUSIONS
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.
Zhang
Ming
M
Department of Radiation Oncology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-5582, USA. mingz@med.umich.edu
Qian
Jun
J
Xing
Xianying
X
Kong
Feng-Ming
FM
Zhao
Lujun
L
Chen
Ming
M
Lawrence
Theodore S
TS
D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D017564:Radiation Pneumonitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016376:Oligonucleotides, Antisense; D011837:Radiation-Protective Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha