Soluble TGFbeta type II receptor gene therapy ameliorates acute radiation-induced pulmonary injury in rats.
OBJECTIVE
To assess whether administration of recombinant human adenoviral vector, which carries soluble TGFbeta1 Type II receptor (TbetaRII) gene, might reduce the availability of active TGFbeta1 and thereby protect the lung from radiation-induced injury.


METHODS
Female Fisher 344 rats were given a single 30 Gy dose of right hemithoracic irradiation 24 h after the injections of control (AdGFP) or treatment (AdexTbetaRII-Fc) vectors. Different end points were assessed to look for lung tissue damage.


RESULTS
There was a significant increase in the plasma level of soluble TbetaRII 24 h and 48 h after injection of treatment vector. In the radiation (RT) + AdexTbetaRII-Fc group, there was a significant reduction in respiratory rate at 4 weeks after treatment as compared to the RT-alone group. Histologic results revealed a significant reduction in lung damage and decrease in the number and activity of macrophages in the RT + AdexTbetaRII-Fc group as compared to the RT-alone group. The tissue level of active TGFbeta1 was significantly reduced in rats receiving RT + AdexTbetaRII-Fc treatment. There was also an upregulation of transmembrane TbetaRII in lung tissue in the RT-alone group as compared to the RT + gene therapy rats.


CONCLUSIONS
This study shows the ability of AdexTbetaRII-Fc gene therapy to induce an increase in circulating levels of soluble receptors, to reduce the tissue level of active TGFbeta1, and consequently to ameliorate acute radiation-induced lung injury.
Rabbani
Zahid N
ZN
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Anscher
Mitchell S
MS
Zhang
Xiuwu
X
Chen
Liguang
L
Samulski
Thaddeus V
TV
Li
Chuan-Yuan
CY
Vujaskovic
Zeljko
Z
D000256:Adenoviridae; D000818:Animals; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D008168:Lung / Q000528:radiation effects*; D017346:Protein Serine-Threonine Kinases; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D011853:Radiobiology; D051381:Rats; D011916:Rats, Inbred F344; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood / Q000378:metabolism*
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II