Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis
Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis
复制标题
DOI：
10.1096/fj.12-219634
复制
发表时间：
2013-04-01
期刊：
影响因子：
4.8
通讯作者：
Natarajan, Viswanathan
中科院分区：
文献类型：
--
作者：
Huang, Long Shuang;Berdyshev, Evgeny;Natarajan, Viswanathan
特发性肺纤维化（IPF）是一种慢性和进行性间质性肺病，其中转化生长因子β（TGF-β）和鞘氨醇-1-磷酸（S1 P）促成纤维化的发病机制。然而，鞘氨醇激酶（SphK）在纤维化过程中的体内贡献尚未被记录。来自IPF患者和SphK 1或SphK 2敲除小鼠以及SphK抑制剂的血液单核细胞的微阵列分析用于评估SphKs在纤维发生中的作用。SphK 1/2的表达与IPF患者的肺功能和生存率呈负相关。此外，IPF患者和博来霉素激发小鼠的肺组织中SphK 1的表达增加。在博来霉素攻击的小鼠中，SphK 1而不是SphK 2的敲低增加了存活率和对肺纤维化的抵抗力。SphK抑制剂的给药降低了博莱霉素诱导的小鼠死亡率和肺纤维化。在博莱霉素诱导的肺纤维化小鼠模型中，SphK 1的敲除或SphK抑制剂的治疗减弱了S1 P的产生和TGF-β的分泌，并伴有肺组织中Smad 2和MAPK磷酸化的减少。在体外，博莱霉素诱导的肺成纤维细胞中SphK 1的表达被发现是TGF-β依赖性的。总之，这些数据表明SphK 1在肺纤维化的病理学中起着关键作用，是一种新的治疗靶点。黄湖，澳-地美国，别尔德舍夫，E.，马修，B.，傅，P.，戈尔什科娃岛一、他，D.，妈妈，W.，诺斯岛，妈，S.- F.、Pendyala，S.，雷迪，S。P.，周，T.，张伟，加尔宗，S.一、加西亚，J. G. N.，Natarajan，V.靶向鞘氨醇激酶1减弱博来霉素诱导的肺纤维化。FASEB J.27，1749-1760（2013）。www.fasebj.org
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease, wherein transforming growth factor beta (TGF-beta) and sphingosine-1-phosphate (S1P) contribute to the pathogenesis of fibrosis. However, the in vivo contribution of sphingosine kinase (SphK) in fibrotic processes has not been documented. Microarray analysis of blood mononuclear cells from patients with IPF and SphK1- or SphK2-knockdown mice and SphK inhibitor were used to assess the role of SphKs in fibrogenesis. The expression of SphK1/2 negatively correlated with lung function and survival in patients with IPF. Also, the expression of SphK1 was increased in lung tissues from patients with IPF and bleomycin-challenged mice. Knockdown of SphK1, but not SphK2, increased survival and resistance to pulmonary fibrosis in bleomycin-challenged mice. Administration of SphK inhibitor reduced bleomycin-induced mortality and pulmonary fibrosis in mice. Knockdown of SphK1 or treatment with SphK inhibitor attenuated S1P generation and TGF-beta secretion in a bleomycin-induced lung fibrosis mouse model that was accompanied by reduced phosphorylation of Smad2 and MAPKs in lung tissue. In vitro, bleomycin-induced expression of SphK1 in lung fibroblast was found to be TGF-beta dependent. Taken together, these data indicate that SphK1 plays a critical role in the pathology of lung fibrosis and is a novel therapeutic target.-Huang, L. S., Berdyshev, E., Mathew, B., Fu, P., Gorshkova, I. A., He, D., Ma, W., Noth, I., Ma, S.-F., Pendyala, S., Reddy, S. P., Zhou, T., Zhang, W., Garzon, S. A., Garcia, J. G. N., Natarajan, V. Targeting sphingosine kinase 1 attenuates bleomycin-induced pulmonary fibrosis. FASEB J. 27, 1749-1760 (2013). www.fasebj.org