Maternal bile acid transporter deficiency promotes neonatal demise.
Maternal bile acid transporter deficiency promotes neonatal demise.
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DOI：
10.1038/ncomms9186
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发表时间：
2015-09-29
影响因子：
16.6
通讯作者：
Schuetz JD
中科院分区：
文献类型：
--
作者：
Zhang Y;Li F;Wang Y;Pitre A;Fang ZZ;Frank MW;Calabrese C;Krausz KW;Neale G;Frase S;Vogel P;Rock CO;Gonzalez FJ;Schuetz JD
妊娠期肝内胆汁淤积症(ICP)与不良的新生儿存活率有关，估计影响全球0.4%至5%的妊娠。在这里，我们显示母体胆汁淤积(由于Abcb11缺乏)在出生后24 小时内由于肺不张引起的肺缺氧而导致所有子代的新生儿死亡，这概括了人类颅内压新生儿的呼吸窘迫。Abcb11缺陷母亲的新生儿肺胆汁酸升高，肺表面活性物质结构改变。母体缺乏Nr1i2加上Abcb11缺乏症显著降低了母体血清胆汁酸浓度，增加了新生儿存活率。我们认为肺内胆汁酸是导致妊娠期肝内胆汁淤积症新生儿肺表面活性物质结构紊乱的关键因素。这些发现对新生儿呼吸衰竭有重要影响，特别是当孕妇胆汁酸在怀孕期间升高时，并突出了可通过治疗干预来改善这种情况的潜在途径和靶点。妊娠期肝内胆汁淤积症导致围产儿死亡的机制尚不完全清楚。在这里，作者表明，核受体和胆汁酸调节因子Nrli2和胆汁转运蛋白Abcb11的缺失显著降低了母体血清胆汁酸水平，改善了新生儿存活率。
Intrahepatic cholestasis of pregnancy (ICP) is associated with adverse neonatal survival and is estimated to impact between 0.4 and 5% of pregnancies worldwide. Here we show that maternal cholestasis (due to Abcb11 deficiency) produces neonatal death among all offspring within 24 h of birth due to atelectasis-producing pulmonary hypoxia, which recapitulates the neonatal respiratory distress of human ICP. Neonates of Abcb11-deficient mothers have elevated pulmonary bile acids and altered pulmonary surfactant structure. Maternal absence of Nr1i2 superimposed on Abcb11 deficiency strongly reduces maternal serum bile acid concentrations and increases neonatal survival. We identify pulmonary bile acids as a key factor in the disruption of the structure of pulmonary surfactant in neonates of ICP. These findings have important implications for neonatal respiratory failure, especially when maternal bile acids are elevated during pregnancy, and highlight potential pathways and targets amenable to therapeutic intervention to ameliorate this condition. The mechanisms underlying perinatal mortality due to intrahepatic cholestasis of pregnancy are not fully understood. Here, the authors show that absence of the nuclear receptor and bile acid regulator Nrli2 and the biliary transporter Abcb11 strongly reduces maternal serum bile acid levels, improving neonatal survival.