Research in Mechanisms of Action Regarding Inhibitory Effects of Interferon-γ and -β in Intracellular Signal Transduction.

目的：特发性肺纤维化（idiopathic pulmonary fibrosis， IPF）是弥漫性肺疾病领域的致死性疾病，但目前尚无改善预后的有效治疗方法。干扰素有望用于肺疾病纤维化疾病的治疗，然而，干扰素-β未能提高IPF的生存率，干扰素-γ相对改善IPF早期的%VC （%VC bb0 60%）。基于这些临床情况，我们探讨干扰素-□在博来霉素诱导肺纤维化中的作用机制。方法：ICR小鼠第0天静脉给予博来霉素，第4周静脉给予干扰素β。注射博来霉素后28 d，进行组织学和化学分析，评价干扰素-β的作用。分析TGF-β1、血栓反应蛋白-1/2的组织分布及含量。结果与讨论：干扰素β□可减弱脯氨酸羟化酶活性，从而抑制肺纤维化。博莱霉素诱导的上皮细胞和细胞外基质中TGF-β1的升高被干扰素-β减弱。血小板反应蛋白-1/2在对照小鼠的血小板中有限，但在博来霉素诱导的纤维化区域的泡沫细胞中存在。体外研究发现，在不刺激的情况下，IFN-g （10-1000ug/ml）不抑制HMg2980肺成纤维细胞株的生长，但抑制TGF-β1诱导的HMg2980细胞株的增殖。这些结果表明，干扰素β□的抗纤维化作用是通过抑制TGF-β及其激活，减少肺组织中血小板-1/2的表达，改变血小板-1/2向泡沫细胞的位置。IFN-β和IFN-γ将在不同机制下抑制成纤维细胞增殖。

Purpose :Though idiopathic pulmonary fibrosis(IPF) is fatal disease in field of diffuse lung diseases, no effective treatment improving prognosis has been reported. Interferons will be promising for treatment in fibrotic disorders in pulmonary disease, however, Interferon-β has been failed to improve survival ratio of IPF and interferon-γ fairly improved %VC in early stage of IPF (%VC>60%). Based on these clinical situations, we investigated mechanism of action of interferon-□ in bleomycin induced pulmonary fibrosis.Methods :Bleomycin at day 0 and interferon-β for 4 weeks were administered intravenously to ICR mice. At 28 days after bleomycin injection, histological and chemical analysis was performed for evaluation of effects of interferon-β. Tissue distribution and amounts of TGF-β1 and thrombospondin-1/2 were analyzed.Results and Discussion :Interferon-β□ attenuated prolylhydroxylase activity, resulting in inhibition of pulmonary fibrosis. Bleomycin-induced increase in TGF-β1 in epithelial cells and extracellular matrix was attenuated by interferon-β. Thrombospondin-1/2 was limited in platelets of control mice, but was present in foamy cells in fibrotic regions induced by bleomycin. In vitro study, IFN-g (10-1000ug/ml) did not inhibit growth of HMg2980 lung fibroblast cell line under no stimulation, but inhibited TGF-β1-induced proliferation of HMg2980 cell line.These findings suggest that the antifibrotic effect of interferon-β□ is inhibition of TGF-βand its activation via decrease in thrombospondin-1/2 in lung tissue and change in location of thrombospondin-1/2 from platelets to foamy cells. IFN-β and IFN-γ will be promising agents in different mechanisms to inhibit fibroblast proliferation.