Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-|[beta]| type II receptor gene

摘要

To investigate whether radiation-induced pneumonitis in the mouse-irradiated lung could be prevented by recombinant adenovirus-mediated soluble transforming growth factor-beta (TGF-) 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+AdCMVsTR 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 9Gy, and then the TGF-1 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- type II receptor (AdCMVsTR), which can bind to TGF- and then block the TGF- receptor-mediated signal transduction. The C57BL/6J mice were intraperitoneally (i.p.) injected with either 5 108 plaque-forming units of AdCMVsTR 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-1 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 9Gy, radiation-induced TGF-1 release in the serum reached the first peak concentration at 12h and then declined. It reached a maximal value at 2 weeks after irradiation. In the BALF, the TGF-1 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 AdCMVsTR 1 week before irradiation could not completely suppress the two peaks of the radiation-induced TGF-1 increase, whereas an injection a week preceding and a week following thoracic irradiation was able to suppress those two peaks thoroughly. The TGF-1 was completely suppressed in the AdCMVsTR-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 (PR-treated mice in comparison to the AdCMVluc-infected and RT-alone mice. Our results demonstrated that TGF-1 plays an important role in radiation pneumonitis, thus suggesting that the adenovirus-mediated overexpression in soluble TGF- type II receptor gene therapy may be a potentially feasible and effective strategy for the prevention of radiation pneumonitis.