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Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-β type II receptor gene

Cancer Gene Therapy volume 13, pages 864–872 (2006)Cite this article

Abstract

To investigate whether radiation-induced pneumonitis in the mouse-irradiated lung could be prevented by recombinant adenovirus-mediated soluble transforming growth factor-beta (TGF-β) type II receptor gene therapy. Radiation fibrosis-prone mice (C57BL/6J) were randomly divided into four groups consisting of a (1) control group (sham-irradiated); (2) radiation (RT)-alone group; (3) RT+AdCMVsTβR group and (4) RT+AdCMVluc group. The RT-alone and sham-irradiated mice were killed at several time points after thoracic irradiation with a single dose of 9 Gy, and then the TGF-β1 concentrations in serum and broncho-alveolar lavage fluid (BALF) were quantified by enzyme-linked immunosorbent assay (ELISA). We used an adenoviral vector expressing a soluble TGF-β type II receptor (AdCMVsTβR), which can bind to TGF-β and then block the TGF-β receptor-mediated signal transduction. The C57BL/6J mice were intraperitoneally (i.p.) injected with either 5 × 108 plaque-forming units of AdCMVsTβR or AdCMVluc, a control adenovirus-expressing luciferase, a week preceding and a week following the X-ray thoracic irradiation. Four weeks after irradiation, the mice were killed and the concentration of TGF-β1 in the serum and BALF were then measured using ELISA and the lung tissue specimens were examined histopathologically. Following thoracic irradiation with a single dose of 9 Gy, radiation-induced TGF-β1 release in the serum reached the first peak concentration at 12 h and then declined. It reached a maximal value at 2 weeks after irradiation. In the BALF, the TGF-β1 concentration was appreciable within the first hour and thereafter declined. It reached a maximal value at 3 days after irradiation. A one-time i.p. injection of AdCMVsTβR 1 week before irradiation could not completely suppress the two peaks of the radiation-induced TGF-β1 increase, whereas an injection a week preceding and a week following thoracic irradiation was able to suppress those two peaks thoroughly. The TGF-β1 was completely suppressed in the AdCMVsTβR-treated mouse serum and BALF; however, no statistical difference was observed in the serum and BALF between the AdCMVluc-infected mice and the control mice at 4 weeks after irradiation (P<0.05). A histopathological examination showed only mild radiation pneumonitis in the irradiated lungs of AdCMVsTβR-treated mice in comparison to the AdCMVluc-infected and RT-alone mice. Our results demonstrated that TGF-β1 plays an important role in radiation pneumonitis, thus suggesting that the adenovirus-mediated overexpression in soluble TGF-β type II receptor gene therapy may be a potentially feasible and effective strategy for the prevention of radiation pneumonitis.

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Acknowledgements

We thank Dr Mizuho Yamada for her valuable help and technical assistance in the animal experiment. We also appreiciate the assistance of Ms Chie Kihara for her help in preparing the manuscript.

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Authors and Affiliations

  1. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Z Haiping, K Takayama, J Uchino, A Harada & Y Nakanishi

  2. Department of Oncology, Shanghai Pneumonology Hospital, Shanghai, China

    Z Haiping & Z Caicun

  3. Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita, Japan

    Y Adachi

  4. Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    S Kura & T Tsuzuki

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  1. Z Haiping
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Correspondence to K Takayama.

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Haiping, Z., Takayama, K., Uchino, J. et al. Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-β type II receptor gene. Cancer Gene Ther 13, 864–872 (2006). https://doi.org/10.1038/sj.cgt.7700959

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