Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation
Blockade of lysophosphatidic acid receptors LPAR1/3 ameliorates lung fibrosis induced by irradiation
复制标题
阻断溶血磷脂酸受体 LPAR1/3 可改善辐射引起的肺纤维化
DOI：
10.1016/j.bbrc.2011.04.084
复制
发表时间：
2011-05-27
影响因子：
3.1
通讯作者：
Jiang, Wei
中科院分区：
文献类型：
--
作者：
Gan, Lu;Xue, Jian-Xin;Jiang, Wei
肺纤维化是肺癌放射治疗常见而严重的并发症，目前尚无有效的治疗方法。越来越多的证据表明，溶血磷脂酸(LPA)及其受体(LPAR)参与了纤维化的发病机制。在此，我们报道了16Gy射线胸部照射诱导的小鼠放射性肺纤维化(RLF)的形成，并伴有LPA释放和LPAR1和LPAR3(LPAR1/3)转录本的明显增加。用双重LPAR1/3拮抗剂VPC12249治疗的小鼠的RLF显著减轻。VPC12249能有效延长动物存活时间，恢复肺组织结构，抑制成纤维细胞聚集，减少胶原沉积。此外，给予VPC12249后，辐射后肺组织中促纤维化细胞因子明显减少，包括转化生长因子131和结缔组织生长因子。在体外，LPA以剂量依赖的方式诱导成纤维细胞的增殖和CTGF的表达，并被LPAR1/3阻断。针对CTCF的siRNA抑制了LPA对成纤维细胞的促增殖作用。综上所述，我们的数据提示LPA-LPAR1/3信号系统通过以CTGF依赖的方式促进成纤维细胞的增殖参与了RLF的发展。LPA-LPAR1/3-CTGF通路可能是RLF治疗的潜在靶点。(C)2011 Elsevier Inc.保留所有权利。
Lung fibrosis is a common and serious complication of radiation therapy for lung cancer, for which there are no efficient treatments. Emerging evidence indicates that lysophosphatidic acid (LPA) and its receptors (LPARs) are involved in the pathogenesis of fibrosis. Here, we reported that thoracic radiation with 16 Gy in mice induced development of radiation lung fibrosis (RLF) accompanied by obvious increases in LPA release and LPAR1 and LPAR3 (LPAR1/3) transcripts. RLF was significantly alleviated in mice treated with the dual LPAR1/3 antagonist, VPC12249. VPC12249 administration effectively prolonged animal survival, restored lung structure, inhibited fibroblast accumulation and reduced collagen deposition. Moreover, profibrotic cytokines in radiation-challenged lungs obviously decreased following administration of VPC12249, including transforming growth factor 131 (TGF beta 1) and connective tissue growth factor (CTGF). In vitro, LPA induced both fibroblast proliferation and CTGF expression in a dose-dependent manner, and both were suppressed by blockade of LPAR1/3. The pro-proliferative activity of LPA on fibroblasts was inhibited by siRNA directed against CTCF. Together, our data suggest that the LPA-LPAR1/3 signaling system is involved in the development of RLF through promoting fibroblast proliferation in a CTGF-dependent manner. The LPA-LPAR1/3-CTGF pathway may be a potential target for RLF therapy. (C) 2011 Elsevier Inc. All rights reserved.