Histopathologic amelioration of fibroproliferative change in rat irradiated lung using soluble transforming growth factor-beta (TGF-beta) receptor mediated by adenoviral vector.
OBJECTIVE
To investigate whether an adenoviral-mediated soluble transforming growth factor-beta (TGF-beta) type II receptor could ameliorate fibroproliferative change in rat irradiated lung.


METHODS
We used an adenoviral vector expressing a soluble TGF-beta receptor (AdT beta-ExR), which adsorbs TGF-beta and inhibits the function of the wild-type receptor as a dominant-negative mutant. Rats were i.v. injected with either 0.5 mL of AdT beta-ExR (1.0 x 10(9) plaque-forming units/mL) or AdLacZ (1.0 x 10(9) plaque-forming units/mL), a control adenovirus expressing bacterial beta-galactosidase, or saline, then 3 days later they received 4-MV X-ray irradiation of 30 Gy in a single fraction to the right lung. Eight weeks after irradiation, the rats were killed, and their right lungs were examined histopathologically. The respiratory rates of all rats were observed with a charge-coupled device video system before the rats were irradiated and killed.


RESULTS
A significant increase in breathing rates was observed in the saline- or AdLacZ-infected rats. The respiratory rate of the AdT beta-ExR-treated rats was significantly lower than that in the saline- or AdLacZ-infected rats. Fibroproliferative change in the irradiated lung was markedly reduced in the AdT beta-ExR-treated rats in comparison with the saline- or AdLacZ-infected rats. With respect to active TGF-beta 1 expression, myofibroblast proliferation, and macrophage/monocyte infiltration, the findings were identical to those for fibroproliferative change.


CONCLUSIONS
Our results indicate that TGF-beta plays a critical role in radiation-induced fibroproliferation of the lung and suggest that the adenoviral-mediated soluble TGF-beta receptor may have potential for use in the amelioration of this intractable pulmonary damage.
Nishioka
Akihito
A
Department of Tumor Radiology, Kochi Medical School, Kochi, Japan. nishioka@kochi-ms.ac.jp
Ogawa
Yasuhiro
Y
Mima
Tatsuo
T
Jin
Yong-Jian
YJ
Sonobe
Hiroshi
H
Kariya
Shinji
S
Kubota
Kei
K
Yoshida
Shoji
S
Ueno
Hikaru
H
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D005822:Genetic Vectors / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D023421:Models, Animal; D017564:Radiation Pneumonitis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051381:Rats; D011916:Rats, Inbred F344; D012119:Respiration; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000627:therapeutic use*; D053781:Transforming Growth Factor beta2; D010948:Viral Plaque Assay
D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2