Sphingolipids in pulmonary fibrosis.
Sphingolipids in pulmonary fibrosis.
复制标题
DOI：
10.1016/j.jbior.2014.09.008
复制
发表时间：
2015-01
影响因子：
--
通讯作者：
Natarajan V
中科院分区：
文献类型：
--
作者：
Huang LS;Natarajan V
特发性肺纤维化(IPF)是一种以肺泡上皮细胞损伤、成纤维细胞/肌成纤维细胞聚集和细胞外基质蛋白沉积为特征的破坏性疾病。1-磷酸鞘氨醇(S1P)是一种天然存在的生物活性脂质，在IPF患者和肺纤维化动物模型的支气管肺泡液和肺组织中水平升高。然而，S1P在肺纤维化发病机制中的作用尚不清楚，S1P由鞘氨醇激酶(SphKs)1和2催化合成，S1P磷酸酶和S1P裂解酶(S1PL)分解代谢调节。通过对IPF患者、SphK1、SphK2或S1PL基因敲除小鼠外周血单个核细胞及SphK抑制剂的基因芯片分析，探讨S1P在肝纤维化中的作用。SphK1的表达与IPF患者的肺功能和生存期呈负相关。此外，IPF患者和博莱霉素攻击小鼠的肺组织中SphK1和S1PL的表达增加。SphK1的基因敲除，而不是SphK2，改善了博莱霉素诱导的小鼠肺纤维化，而S1PL(SGPL1+/−)的缺失则加强了博莱霉素攻击后的纤维化。转化生长因子-β上调人肺成纤维细胞SphK1和S1PL的表达，下调SphK1或用SphK抑制剂处理可抑制S1P的产生和转化生长因子-β介导的信号转导。S1PL过表达抑制博莱霉素诱导的转化生长因子-β分泌，并通过自噬调节S1P介导的人肺成纤维细胞分化。博莱霉素激发后第8天给予SphK1抑制剂可减少博莱霉素诱导的死亡率和肺纤维化。我们的结果提示SphK1和S1PL在肺纤维化的病理过程中起着关键作用，并可能成为新的治疗靶点。
Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by alveolar epithelial cell injury, accumulation of fibroblasts/myofibroblasts and deposition of extracellular matrix proteins. Levels of sphingosine-1-phosphate (S1P), a naturally occurring bioactive lipid, are elevated in bronchoalveolar fluids and lung tissues from IPF patients and animal models of pulmonary fibrosis. However, the in vivo contribution of S1P, regulated by its synthesis catalyzed by Sphingosine kinases (SphKs) 1 & 2 and catabolism by S1P phosphatases and S1P lyase (S1PL), in the pathogenesis of pulmonary fibrosis is not well defined. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1-, SphK2- or S1PL-knockout mice and SphK inhibitor were used to assess the role of S1P in fibrogenesis. The expression of SphK1 negatively correlated with lung function and survival of patients with IPF. Further, the expressions of SphK1 and S1PL were increased in lung tissues from patients with IPF and bleomycin-challenged mice. Genetic knockdown of SphK1, but not SphK2, ameliorated bleomycin-induced pulmonary fibrosis in mice while deletion of S1PL (SGPL1+/−) in mice potentiated fibrosis post-bleomycin challenge. TGF-β increased the expression of SphK1 and S1PL in human lung fibroblasts and knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-β mediated signal transduction. Overexpression of S1PL attenuated bleomycin-induced TGF-β secretion and S1P mediated differentiation of human lung fibroblasts through regulation of autophagy. Administration of SphK1 inhibitor 8 days post-bleomycin challenge reduced bleomycin-induced mortality and pulmonary fibrosis. Our results suggest that SphK1 and S1PL play critical roles in the pathology of lung fibrosis and may be novel therapeutic targets.