Effect of Interferon- γ on Radiation-induced Lung Injury

Research Project

Project/Area Number	13670968
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Single-year Grants
Section	一般
Research Field	Radiation science
Research Institution	Tokai University
Principal Investigator	TANIGAKI Toshimori Tokai University, School of Medicine, Assistant Professor, 医学部, 講師 (90246091)
Co-Investigator(Kenkyū-buntansha)	TSUJI Chizuko Tokai University, School of Medicine, Assistant Professor, 医学部, 講師 (80130079) SHIOYA Sumie Tokai University, School of Medicine, Associate Professor, 医学部, 助教授 (20102840)
Project Period (FY)	2001 – 2002
Project Status	Completed (Fiscal Year 2002)
Budget Amount *help	¥1,500,000 (Direct Cost: ¥1,500,000) Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000) Fiscal Year 2001: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywords	pulmonary fibrosis / radiation-induced lung injury / interferon-γ / NMR relaxation time / TGF-β1 / procollagen α1(I) / connective-tissue growth factor / 投与開始時期 / 放射線 / T_1 / mRNA / TGFβ_1
Research Abstract	Radiation-induced fibrosis (RF) is one of limiting factors in radiation therapy for thoracic malignancies and can be cured by no means. IFN-γ has been shown to inhibit collagen synthesis in vitro and in vivo including clinical idiopathic pulmonary fibrosis (IPF). We first examined effect of IFN-γ on radiation fibrosis and on TGF-β1 and connective-tissue growth factor (CTGF) mRNA levels in lung tissue that received 20 Gy in one fraction in the left hemithorax. Wistar rats were divided into 3 groups: control (C), radiation control (RC) and radiation + treatments (RT). The RT group was treated with methylprednisolone 21-acetate (2mg/kg, i.m.) 6 hr before and once a week until Week 8 and with IFN-γ (4μg/kg, s.c.) three times a week from Week 4 to 24. Experiments were performed at Week 8, 16 and 24. Fibrotic change was evaluated with histologic specimens and using NMR relaxation time (T1) of the lung tissues and there was no significant difference in them. In the mRNA levels, there was no s … More ignificant difference except for CTGF that was increased significantly in the RC group only at Week 8. These results show that IFN-γ does not attenuate RF in rat and seems to be related to the irradiation dosage, steroid and timing to begin IFN-γ administration. We then examined the effect of IFN-γ on RPF with 10 Gy without steroid. Wistar rats were divided into 5 groups: a control group (C), a radiation control group (RC), a pre-treated radiation group (Pre-RT), a group with treatment begun 1 week after radiation (1w-RT) and a group with treatment begun 2 weeks after radiation (2w-RT). The RT groups were treated with IFN-γ (4μg/kg, s.c.) three times a week. Fibrotic change was evaluated at Week 16 using T1 of lung tissues which correlates inversely with the degree of fibrosis. Irradiation shortened T1 significantly, an effect mitigated by IFN-γ, only in the Pre-RT and 1w-RT groups. We then measured TGF-β1, CTGF, and procollagen α 1(I) mRNA levels in lung tissue at Week 1 and 2 to elucidate the mechanism of the IFN effect. Irradiation increased CTGF and procollagen α 1(I) mRNA levels significantly at Week 1 and 2. IFN-γ reduced TGF-β1 and procollagen α 1(I) mRNA levels in the Pre-RT and 1w-RT groups at Week 2. These results suggest that attenuation of RPF at Week 16 as measured by T1 may be related to reduction of TGF-β1 and procollagen α 1(I) mRNA levels at Week 2 induced by IFN-γ administered up to 1 week after irradiation. Less