Inhibition of Sphingosine Kinase Prevents Lipopolysaccharide-Induced Preterm Birth and Suppresses Proinflammatory Responses in a Murine Model
Inhibition of Sphingosine Kinase Prevents Lipopolysaccharide-Induced Preterm Birth and Suppresses Proinflammatory Responses in a Murine Model
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DOI：
10.1016/j.ajpath.2014.10.026
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发表时间：
2015-03-01
影响因子：
6
通讯作者：
Reznik, Sandra E.
中科院分区：
文献类型：
--
作者：
Vyas, Vibhuti;Ashby, Charles R., Jr.;Reznik, Sandra E.
早产发生在所有出生的12%，并占近一半的长期神经系统发病率和围产期死亡率的60%至80%。尽管产科和妇产科取得了进步，但自1990年以来，早产率增加了约12%。自发性早产最常见的原因是感染。一些证据表明内皮素-1作为子宫肌层平滑肌收缩剂和促炎介质的作用。内皮素-1激活磷脂酶C途径，导致蛋白激酶C的激活，进而激活鞘氨醇激酶（SphK）。最近已经显示SphK的抑制控制与脓毒症相关的促炎反应。我们在此首次表明，SphK抑制可预防小鼠模型中炎症相关的早产。SphK抑制剂通过抑制促炎细胞因子肿瘤坏死因子α、IL-1 β和IL-6以及减少胎盘迷路中的多形核炎性细胞来挽救早产幼崽。此外，我们推测，SphK的抑制导致抑制内皮素转换酶-1的表达，表明内皮素转换酶Vendothelin 1-SphK正反馈环的存在。这项工作介绍了一种新的方法来控制感染引发的早产，这种情况没有有效的治疗方法。
Premature delivery occurs in 12% of all births, and accounts for nearly half of Long-term neurological morbidity, and 60% to 80% of perinatal mortality. Despite advances in obstetrics and neonatology, the rate of premature delivery has increased approximately 12% since 1990. The single most common cause of spontaneous preterm birth is infection. Several lines of evidence have demonstrated the role of endothelin-1 as both a constrictor of uterine myometrial smooth muscle and a proinflammatory mediator. Endothelin-1 activates the phospholipase C pathway, leading to activation of protein kinase C and, in turn, sphingosine kinase (SphK). The inhibition of SphK has been recently shown to control the proinflammatory response associated with sepsis. We show herein, for the first time, that SphK inhibition prevents inflammation-associated preterm birth in a murine model. Rescue of pups from premature abortion with an SphK inhibitor occurs by suppression of the proinflammatory cytokines tumor necrosis factor a, Il-1 beta, and Il-6 and attenuation of polymorphonuctear inflammatory cells into the placental labyrinth. Moreover, we postulate that inhibition of SphK leads to suppression of endotheLin-converting enzyme-1 expression, indicating the presence of an endothelin-converting enzyme Vendothelin 1-SphK positive feedback loop. This work introduces a novel approach for the control of infection-triggered preterm Labor, a condition for which there is no effective treatment.