Effect of Interferon- γ on Radiation-induced Lung Injury

放射诱导纤维化（RF）是胸部恶性肿瘤放射治疗的限制因素之一，无法治愈。IFN-γ已被证明在体外和体内抑制胶原合成，包括临床特发性肺纤维化（IPF）。我们首先检测了IFN-γ对辐射纤维化的影响，以及对接受20 Gy左半胸部分肺组织中TGF-β1和结缔组织生长因子（CTGF） mRNA水平的影响。Wistar大鼠分为3组：对照组(C)、放射对照组（RC）和放射+治疗组（RT）。RT组给予21-醋酸甲基强的松龙（2mg/kg, ig）治疗。IFN-γ (4μg/kg, s.c)，从第4周到第24周，每周3次。实验于第8周、第16周和第24周进行。采用肺组织的组织学标本和核磁共振弛豫时间（T1）评价肺组织的纤维化变化，两者无显著性差异。在mRNA水平上，除CTGF在RC组仅在第8周显著升高外，其他差异均无统计学意义。这些结果表明，IFN-γ不会减弱大鼠的RF，似乎与辐照剂量、类固醇和开始给药IFN-γ的时间有关。然后我们检测了IFN-γ在不使用类固醇的情况下对10 Gy RPF的影响。Wistar大鼠分为5组：对照组(C)、放疗对照组（RC）、放疗前治疗组（Pre-RT）、放疗后1周开始治疗组（1w-RT）和放疗后2周开始治疗组（2w-RT）。RT组给予IFN-γ (4μg/kg, s.c)治疗，每周3次。在第16周使用肺组织T1评估纤维化改变，T1与纤维化程度呈负相关。放疗显著缩短T1， IFN-γ仅在Pre-RT组和1w-RT组中减轻了这一作用。然后，我们在第1周和第2周测量肺组织中TGF-β1、CTGF和前胶原α 1(I) mRNA水平，以阐明IFN作用的机制。在第1周和第2周，辐照显著提高CTGF和前胶原α 1(I) mRNA水平。在第2周，IFN-γ降低了Pre-RT组和1w-RT组TGF-β1和前胶原α 1(I) mRNA水平。这些结果表明，通过T1测量的RPF在第16周的衰减可能与在照射后长达1周的IFN-γ诱导的第2周TGF-β1和前胶原α 1(I) mRNA水平的降低有关。少

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