Synthetic Analogs of FTY720 [2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] Differentially Regulate Pulmonary Vascular Permeability in Vivo and in Vitro
Synthetic Analogs of FTY720 [2-Amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] Differentially Regulate Pulmonary Vascular Permeability in Vivo and in Vitro
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DOI：
10.1124/jpet.109.153544
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发表时间：
2009-10-01
影响因子：
3.5
通讯作者：
Dudek, S. M.
中科院分区：
文献类型：
--
作者：
Camp, S. M.;Bittman, R.;Dudek, S. M.
需要新的疗法来解决在炎性疾病如急性肺损伤（ALI）中发生的血管内皮细胞（EC）屏障破坏。我们先前证明了1-磷酸鞘氨醇（S1 P）和结构相似的化合物FTY 720 [2-氨基-2-（2-[4-辛基苯基]乙基）-1，3-丙二醇]在炎症性肺损伤中的有效屏障增强作用。在这项研究中，我们研究了几种新型FTY 720类似物减少血管渗漏的治疗潜力。与S1 P和FTY 720类似，FTY 720膦酸酯和烯膦酸酯类似物的（R）-和（S）-对映体在体外产生持续的EC屏障增强，如通过跨内皮电阻（TER）的增加所见。相反，FTY 720-区域异构体类似物的（R）-和（S）-对映异构体以剂量依赖性方式破坏EC屏障完整性。屏障增强FTY 720类似物在体外显示出更宽的保护浓度范围（1-50 μ M）和比S1 P或FTY 720更大的效力。与FTY 720诱导的EC屏障增强相反，S1 P和FTY 720类似物在与皮质肌动蛋白环形成相关的几分钟内显著增加TER。与S1 P不同，这些FTY 720类似物表现出差异磷酸化作用，而不改变细胞内钙水平。抑制剂研究表明，这些类似物的屏障增强涉及通过G（i）偶联受体、酪氨酸激酶和脂筏的信号传导。与这些体外反应一致，FTY 720的（S）-膦酸酯类似物显著降低脂多糖介导的ALI小鼠模型中肺泡和血管通透性的多个指数（白细胞计数没有显著改变）。这些结果证明FTY 720类似物在体外和体内显著降低肺血管渗漏和炎症的能力。
Novel therapies are needed to address the vascular endothelial cell (EC) barrier disruption that occurs in inflammatory diseases such as acute lung injury (ALI). We previously demonstrated the potent barrier-enhancing effects of both sphingosine 1-phosphate (S1P) and the structurally similar compound FTY720 [2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol] in inflammatory lung injury. In this study, we examined the therapeutic potential of several novel FTY720 analogs to reduce vascular leak. Similar to S1P and FTY720, the (R)- and (S)-enantiomers of FTY720 phosphonate and enephosphonate analogs produce sustained EC barrier enhancement in vitro, as seen by increases in transendothelial electrical resistance (TER). In contrast, the (R)- and (S)-enantiomers of FTY720-regioisomeric analogs disrupt EC barrier integrity in a dose-dependent manner. Barrier-enhancing FTY720 analogs demonstrate a wider protective concentration range in vitro (1-50 mu M) and greater potency than either S1P or FTY720. In contrast to FTY720-induced EC barrier enhancement, S1P and the FTY720 analogs dramatically increase TER within minutes in association with cortical actin ring formation. Unlike S1P, these FTY720 analogs exhibit differential phosphorylation effects without altering the intracellular calcium level. Inhibitor studies indicate that barrier enhancement by these analogs involves signaling via G(i)-coupled receptors, tyrosine kinases, and lipid rafts. Consistent with these in vitro responses, the (S)-phosphonate analog of FTY720 significantly reduces multiple indices of alveolar and vascular permeability in a lipopolysaccharide-mediated murine model of ALI (without significant alterations in leukocyte counts). These results demonstrate the capacity for FTY720 analogs to significantly decrease pulmonary vascular leakage and inflammation in vitro and in vivo.