Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis.
Inhibition of the CXCL12/CXCR4-axis as preventive therapy for radiation-induced pulmonary fibrosis.
复制标题
DOI：
10.1371/journal.pone.0079768
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Shim H
中科院分区：
文献类型：
--
作者：
Shu HK;Yoon Y;Hong S;Xu K;Gao H;Hao C;Torres-Gonzalez E;Nayra C;Rojas M;Shim H
由辐射引起的毁灭性晚期损伤是肺纤维化。这种风险可能会限制照射量并影响潜在的治愈性治疗。因此，开发一种预防这种毒性的治疗方法可能对该患者人群有很大的益处。趋化因子受体CXCR 4被其配体基质细胞衍生因子1（SDF-1/CXCL 12）激活可能在辐射诱导的肺纤维化的发展中起重要作用。在这里，我们测试了MSX-122，一种新的小分子和部分CXCR 4拮抗剂，是否可以阻止这种纤维化过程的发展。所用的放射诱导的肺纤维化模型是C57 BL/6小鼠，其整个胸部或右半胸部被照射至20戈伊。我们的联体模型包括将表达GFP的转基因C57 BL/6小鼠与随后被照射的野生型小鼠连接，以评估GFP+骨髓来源的祖细胞向照射的肺的迁移。用ELISA法测定照射后支气管肺泡灌洗液（BALF）和血清中CXCL 12的水平。RNA酶保护实验检测照射后肺组织CXCR 4和CXCL 12 mRNA的表达。每天用AMD 3100（一种已确立的CXCR 4拮抗剂）、MSX-122及其相应的溶剂处理辐照小鼠，以确定药物处理对纤维化发展的影响。通过连续CT和组织学评估纤维化。照射后，BALF和血清中CXCL 12水平增加，照射肺内CXCR 4 mRNA相应升高，这与CXCR 4+细胞群的募集一致。使用我们的联体模型，我们证明了CXCR 4+骨髓来源的间充质干细胞的招募，根据标记物表达鉴定，照射肺。最后，接受MSX-122的辐射小鼠肺纤维化的发展显著减少，而AMD 3100没有显著抑制这种纤维化过程。通过药物如MSX-122抑制CXCR 4可以减轻潜在的辐射诱导的肺损伤，为需要胸部照射的患者提供未来的治疗机会。
A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12) may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process. The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF) and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process. CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation.
登录
查看更多内容
影响因子：
120.1
作者：
De Clercq, E
通讯作者：
De Clercq, E
DOI：
10.1513/pats.200512-133tk
发表时间：
2006-06-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Lama, Vibha N;Phan, Sem H
通讯作者：
Phan, Sem H
影响因子：
15.9
作者：
Phillips, RJ;Burdick, MD;Strieter, RM
通讯作者：
Strieter, RM
影响因子：
11.2
作者：
Xu, Kaiming;Shu, Hui-Kuo G.
通讯作者：
Shu, Hui-Kuo G.
影响因子：
15.9
作者：
Hashimoto, N;Jin, H;Phan, SH
通讯作者：
Phan, SH