Targeting sphingosine-1-phosphate signaling in lung diseases.
Targeting sphingosine-1-phosphate signaling in lung diseases.
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DOI：
10.1016/j.pharmthera.2016.09.008
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发表时间：
2016-12
影响因子：
13.5
通讯作者：
Natarajan, Viswanathan
中科院分区：
文献类型：
--
作者：
Ebenezer, David L.;Fu, Panfeng;Natarajan, Viswanathan
关键词：
鞘氨醇-1-磷酸（S1 P）是一种简单的生物活性鞘脂代谢产物，在细胞内和细胞外的各种细胞过程中起着关键作用，如增殖、存活、迁移、炎症、血管生成和内皮屏障完整性。细胞S1 P水平低，并受到其合成和降解的严格调节。鞘氨醇激酶（SphKs）1和2催化鞘氨醇的ATP依赖性磷酸化为S1 P，而降解由S1 P磷酸酶和脂质磷酸磷酸酶催化的可逆去磷酸化以及鞘氨醇-1-磷酸裂解酶（S1 PL）不可逆降解为十六烯醛和乙醇胺磷酸介导。作为特异性G蛋白偶联受体S1 P 1 -5的配体，S1 P 1 -5在不同细胞类型中差异表达，S1 P产生下游信号，在发育和疾病相关病理学中发挥关键作用。除了在细胞外作用于位于质膜上的受体之外，S1 P还可以在细胞内作用，独立于S1 P1 -5，影响钙稳态和细胞增殖。SphKs /S1 P/S1 PL代谢途径涉及许多人类病理学，包括呼吸系统疾病，从而提高了操纵细胞内S1 P水平可以提供改善肺部疾病的治疗潜力的可能性。本文综述了靶向S1 P信号转导和代谢酶的小分子抑制剂、受体激动剂和拮抗剂在肺部疾病治疗中的应用前景。
Sphingosine-1- phosphate (S1P), a simple, bioactive sphingolipid metabolite, plays a key role, both intracellularly and extracellularly, in various cellular processes such as proliferation, survival, migration, inflammation, angiogenesis, and endothelial barrier integrity. The cellular S1P level is low and is tightly regulated by its synthesis and degradation. Sphingosine Kinases (SphKs) 1 and 2, catalyze the ATP-dependent phosphorylation of sphingosine to S1P, while the degradation is mediated by the reversible dephosphorylation catalyzed by the S1P phosphatases and lipid phosphate phosphatases and the irreversible degradation to hexadecenal and ethanolamine phosphate by sphingosine-1-phosphate lyase (S1PL). As a ligand for specific G-protein-coupled receptors, S1P1–5, which are differentially expressed in different cell types, S1P generates downstream signals that play crucial role in developmental and disease related pathologies. In addition to acting extracellularly on receptors located on the plasma membrane, S1P can also act intracellularly, independently of S1P1–5, affecting calcium homeostasis and cell proliferation. The SphKs /S1P /S1PL metabolic pathway is implicated in numerous human pathologies including respiratory disorders, thereby raising the possibility that manipulating intracellular S1P levels could offer therapeutic potential in ameliorating lung diseases. This review focuses on the prospects of targeting S1P signaling and S1P metabolizing enzymes using small molecule inhibitors, receptor agonists, and antagonists in the treatment of lung diseases.
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