N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth.
N,N-dimethylacetamide regulates the proinflammatory response associated with endotoxin and prevents preterm birth.
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DOI：
10.1016/j.ajpath.2013.05.006
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发表时间：
2013-08
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通讯作者：
Sruthi Sundaram;C. Ashby;Ryan Pekson;Vaishali Sampat;R. Sitapara;L. Mantell;Chih-Hung Chen;H. Yen;K. Abhichandani;S. Munnangi;Nikhil Khadtare;R. Stephani;S. Reznik
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作者：
Sruthi Sundaram;C. Ashby;Ryan Pekson;Vaishali Sampat;R. Sitapara;L. Mantell;Chih-Hung Chen;H. Yen;K. Abhichandani;S. Munnangi;Nikhil Khadtare;R. Stephani;S. Reznik
促炎反应导致各种类型的病理途径，包括早产的发生。在美国，早产发生在12%的分娩中，导致超过70%的围产期发病率和死亡率。自发性早产最常见的原因是母亲的宫内感染。越来越多的证据表明，促炎细胞因子的释放在炎症相关性早产的发病机制中起着关键作用。我们发现，常见的有机溶剂N，N-二甲基乙酰胺(DMA)可以防止定时妊娠C57BL/6胚胎日(E)15.5小鼠内毒素诱导的早产，并以剂量依赖的方式将其幼鼠从自然流产中拯救出来，剂量低于目前临床使用的剂量。我们还提供了组织学证据，表明DMA通过显著减轻胎盘组织中的炎性细胞浸润来抑制内毒素引发的促炎反应。此外，从我们的小鼠模型中获得的胎盘组织的免疫印迹分析显示，DMA介导的致炎细胞因子IL-1β、肿瘤坏死因子α和IL-6的表达受到调节，调节性炎症细胞因子IL-10的表达增加。通过在体外研究中的使用，我们提供了DMA抑制巨噬细胞功能以及这种小分子阻止核因子-kB核转位的证据。这些结果表明，DMA代表了一种新发现的、无毒的治疗广泛的炎症性疾病的方法。
The proinflammatory response leads to various types of pathologic pathways, including the development of preterm birth. Preterm birth occurs in 12% of deliveries in the United States and causes more than 70% of perinatal morbidity and mortality. The most common cause of spontaneous preterm birth is intrauterine infection in the mother. There is accumulating evidence indicating that the release of proinflammatory cytokines plays a critical role in the pathogenesis of inflammation-associated premature delivery. We found that the common organic solvent,N,N-dimethylacetamide (DMA), prevents endotoxin-induced preterm birth in timed pregnant C57BL/6 embryonic day (E)15.5 mice and rescues their pups from spontaneous abortion at doses many-fold lower than those currently used clinically and in a dose-dependent fashion. We also provide histologic evidence that DMA suppresses the endotoxin-triggered proinflammatory response by significantly attenuating inflammatory cell infiltration of placental tissue. Furthermore, immunoblotting analysis of placental tissue harvested from our murine models revealed DMA-mediated regulation of expression of the proinflammatory cytokines IL-1β, tumor necrosis factor α, and IL-6, and increased expression of the regulatory inflammatory cytokine IL-10. By usingin vitrostudies, we provide evidence that DMA suppresses macrophage function and that this small molecule prevents nuclear translocation of nuclear factor-kB. These results suggest that DMA represents a newly discovered, nontoxic therapy for a broad range of inflammatory disorders.