Effect of Interferon- γ on Radiation-induced Lung Injury

放射性纤维化是胸部恶性肿瘤放射治疗的限制因素之一，目前尚无治愈的方法。干扰素-γ在体外和体内均有抑制胶原合成的作用，包括临床上的特发性肺纤维化。我们首先检测了干扰素-γ对放射性纤维化的影响，以及对左半胸20Gy一次照射后肺组织转化生长因子-β1和结缔组织生长因子基因表达的影响。将Wistar大鼠随机分为3组：对照组(C)、照射对照组(RC)和照射+治疗组(RT)。RT组于治疗前6小时肌注甲基强的松龙2 mg/kg，每周1次，直至第8周，同时给予干扰素-γ(4μg/kg，S.C.)。从第4周到第24周，每周三次。实验分别于第8、16、24周进行。用组织学标本和核磁共振弛豫时间(T1)评价肺组织的纤维化改变，两者无显著差异。在基因水平上，没有发现S的…上述结果表明，干扰素-γ对大鼠RF无明显的抑制作用，且与照射剂量、激素及开始给药的时间有关。然后，我们观察了干扰素-γ对10GyRPF的影响。将Wistar大鼠随机分为5组：对照组(C)、照射对照组(RC)、照射前放疗组(Pre-RT)、照射后1周开始治疗组(1w-RT)和照射后2周开始治疗组(2w-RT)。RT组给予干扰素-γ(4μg/kg，皮下注射)。一周三次。在第16周，用肺组织的T1来评估纤维化的变化，这与纤维化的程度成反比。放疗后T1显著缩短，而干扰素-γ对T1的影响仅在放疗前和放疗后1w组明显减轻。分别于1周和2周检测肺组织中转化生长因子-β-1、结缔组织生长因子和前胶原α-1(I)的基因表达水平，以阐明干扰素的作用机制。照射后1周和2周，照射组CTGF1(I)和前胶原α1(I)m RNA水平显著升高，而干扰素-γ在照射后2周降低Tf-β1和前胶原α1(I)m RNA水平。上述结果提示，放射治疗后16周时T1值的降低可能与干扰素-β在照射后1周引起2周时α-γ和前胶原GFP 1(I)m RNA水平降低有关。较少

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