Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism.
Perinatal Endotoxemia Induces Sustained Hepatic COX-2 Expression through an NFκB-Dependent Mechanism.
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DOI：
10.1159/000445541
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发表时间：
2016
影响因子：
5.3
通讯作者：
Wright CJ
中科院分区：
文献类型：
--
作者：
McKenna S;Eckman M;Parker A;Bok R;Hurt KJ;Wright CJ
暴露于围产期感染与早产并发多种疾病有关。相对不成熟的先天免疫反应如何促成这一点尚不清楚。我们试图确定围产期内毒素血症的先天性免疫应答是否通过NFκB依赖性机制诱导了环氧化酶-2（考克斯-2）表达的独特模式。在围产期（e15，e19，P0）或成人内毒素血症后评估肝和肺考克斯-2 mRNA表达。通过胞浆抑制蛋白降解和亚单位核转位来评估肝脏NFκB活性。免疫组织化学和分离的细胞制备物测定肝巨噬细胞考克斯-2表达，并检测NFκB活性的药理学和遗传抑制作用。与暴露于内毒素的成年人相比，围产期内毒素血症诱导持续的肝巨噬细胞考克斯-2表达和NFκB活性。分离的肝巨噬细胞和免疫组化显示，LPS诱导的考克斯-2表达增强，对药理学和遗传学方法减弱NFκB活性敏感。最后，药物抑制新生小鼠内毒素血症诱导的NFκB活性可阻止肝脏NFκB活性并减弱考克斯-2表达。我们的研究结果表明，内毒素血症时新生儿肝脏NFκB活性和考克斯-2表达持续存在，这支持了围产期先天性免疫反应的增强。这可能代表先天免疫反应与早产相关疾病的发病机制之间的联系。
Exposure to perinatal infection is associated with multiple morbidities complicating preterm birth. How a relatively immature innate immune response contributes to this is unknown. We sought to determine if the perinatal innate immune response to endotoxemia induces a unique pattern of cyclooxygenase-2(COX-2) expression via an NFκB dependent mechanism. Hepatic and pulmonary COX-2 mRNA expression was assessed following perinatal(e15, e19, P0) or adult endotoxemia. Hepatic NFκB activity was assessed by cytosolic inhibitory protein degradation and subunit nuclear translocation. Immunohistochemistry and isolated cell preparations determined hepatic macrophage COX-2 expression, and the effect of pharmacologic and genetic inhibition of NFκB activity was tested. Perinatal endotoxemia induced sustained hepatic macrophage COX-2 expression and NFκB activity compared to exposed adults. Isolated hepatic macrophages and immunohistochemistry demonstrated enriched LPS-induced COX-2 expression that was sensitive to pharmacologic and genetic approaches to attenuate NFκB activity. Finally, pharmacologic inhibition of endotoxemia-induced NFκB activity in neonatal mice prevented hepatic NFκB activity and attenuated COX-2 expression. Our findings of sustained neonatal hepatic NFκB activity and COX-2 expression in response to endotoxemia support a robust perinatal innate immune response. This may represent a link between the innate immune response and the pathogenesis of diseases associated with preterm birth.
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