Prevention of radiation-induced pulmonary fibrosis by blockade of transforming growth factor-beta (TGF-β) signaling

A Nishioka, MD,a Y Ogawa, MD,a S Kariya, MD,a S Yoshida, MD,a H Ueno, PhD,b

aDepartment of Radiology, Kochi Medical School, Nankoku, kochi Japan, bDepartment of Biochemistry and Molecular Pathophysiology, University of Occupational and Environmental Health, School of Medicine, Kitakyusyu, Fukuoka Japan

AIM: Radiation-induced pulmonary fibrosis is a major complication of chest irradiation. An effective method for its prevention, however, has not yet been developed. Recently, transforming growth factor-β1 (TGF-β1) has been considered to play a key role in the fibroproliferative change of the irradiated lung. In this study, we examined whether specific blockade of TGF-β signaling prevents radiation-induced pulmonary fibrosis in the rat. METHODS: To block all the diverse signaling of TGF-β, we used an adenoviral vector to over-express a truncated type II TGF-β receptor (AdTβ-ExR) that acts as a dominant-negative receptor. The rats were divided into three groups: normal control (C), radiation (R), and radiation plus blockade of TGF-β signaling with adenovirus (R+Ad). Each rat in the R group received 30 Gy irradiation in the unilateral lung. Each rat in the R+Ad group was pretreated with AdTβ-ExR three days before irradiation with the same doses of the R group. Eight weeks after irradiation, the rats in each group were histopathologically investigated for fibrotic change and TGF-β1 expression in the lung. RESULTS: Pulmonary fibrosis and TGF-β1 expression in the R+Ad group rats were markedly reduced compared with that in the rats in the R group. CONCLUSIONS: Our data indicate that TGF-β does play an important role in the establishment of radiation-induced pulmonary fibrosis, and that blockade of TGF-β signaling is effective for its prevention.

KEY WORDS: gene therapy, adenoviral vector, truncated type II TGF-&beta, receptor, histopathological investigation.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Novel Therapies, Part 1.

This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.