Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema
Stimulation of Sphingosine 1-Phosphate Signaling as an Alveolar Cell Survival Strategy in Emphysema
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DOI：
10.1164/rccm.200906-0826oc
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发表时间：
2010-02-15
影响因子：
24.7
通讯作者：
Petrache, Irina
中科院分区：
文献类型：
--
作者：
Diab, Khalil J.;Adamowicz, Jeremy J.;Petrache, Irina
原理：血管内皮生长因子受体（VEGFR）抑制会增加肺泡肺结构细胞中的神经酰胺，引发细胞凋亡和肺泡破坏，形态上类似于肺气肿。内源性神经酰胺增加的影响可被1 - 磷酸鞘氨醇（S1P）抵消，S1P是神经酰胺代谢的一种促存活副产物。
目的：我们的工作目的是研究肺气肿的VEGFR抑制模型中的鞘氨醇 - S1P - S1P受体轴，并确定刺激S1P信号传导是否足以在功能上拮抗肺泡腔扩大。
方法：在小鼠中进行VEGFR阻断的同时，通过使用S1P前体鞘氨醇、S1P激动剂FTY720或S1P受体 - 1（S1PR1）激动剂SEW2871进行治疗来增强S1P信号传导。结果包括鞘氨醇激酶 - 1 RNA表达和活性、通过液相色谱 - 串联质谱联用测量鞘脂、对促存活信号通路进行免疫印迹、半胱天冬酶 - 3活性和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记测定以及气腔形态测量。
测量和主要结果：与先前报道的神经酰胺合成的从头激活一致，VEGFR抑制引发肺中神经酰胺、二氢神经酰胺和二氢鞘氨醇增加，但不改变鞘氨醇激酶活性或S1P水平。给予鞘氨醇降低了肺中神经酰胺与S1P的比率，并抑制了肺泡腔扩大，同时激活了促存活信号通路并减少了肺实质细胞凋亡。鞘氨醇显著对抗培养的肺内皮细胞中神经酰胺诱导的凋亡，但对上皮细胞无此作用。FTY720或SEW2871重现了鞘氨醇对气腔扩大的保护作用，同时减轻了VEGFR抑制剂诱导的肺细胞凋亡。
结论：旨在增强S1P - S1PR1信号传导的策略可能对改善肺气肿发展的凋亡机制有效。
Rationale: Vascular endothelial growth factor receptor (VEGFR) inhibition increases ceramides in lung structural cells of the alveolus, initiating apoptosis and alveolar destruction morphologically resembling emphysema. The effects of increased endogenous ceramides could be offset by sphingosine 1-phosphate (S1P), a prosurvival by-product of ceramide metabolism.Objectives: The aims of our work were to investigate the sphingosine-S1P-S1P receptor axis in the VEGFR inhibition model of emphysema and to determine whether stimulation of SI P signaling is sufficient to functionally antagonize alveolar space enlargement.Methods: Concurrent to VEGFR blockade in mice, S1P signaling augmentation was achieved via treatment with the S1P precursor sphingosine, S1P agonist FTY720, or S1P receptor-1 (S1PR1)agonist SEW2871. Outcomes included sphingosine kinase-1 RNA expression and activity, sphingolipid measurements by combined liquid chromatography-tandem mass spectrometry, immunoblotting for prosurvival signaling pathways, caspase-3 activity and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays, and airspace morphometry.Measurements and Main Results: Consistent with previously reported de novo activation of ceramide synthesis, VEGFR inhibition triggered increases in lung ceramides, dihydroceramides, and dihydrosphingosine, but did not alter sphingosine kinase activity or S1P levels. Administration of sphingosine decreased the ceramide-to-SI P ratio in the lung and inhibited alveolar space enlargement, along with activation of prosurvival signaling pathways and decreased lung parenchyma cell apoptosis. Sphingosine significantly opposed ceramide-induced apoptosis in cultured lung endothelial cells, but not epithelial cells. FTY720 or SEW2871 recapitulated the protective effects of sphingosine on airspace enlargement concomitant with attenuation of VEGFR inhibitor-induced lung apoptosis.Conclusions: Strategies aimed at augmenting the S1P-S1PR1 signaling may be effective in ameliorating the apoptotic mechanisms of emphysema development.