Zhang Yuanyuan, Li Fei, Wang Yao, Pitre Aaron, Fang Zhong-Ze, Frank Matthew W, Calabrese Christopher, Krausz Kristopher W, Neale Geoffrey, Frase Sharon, Vogel Peter, Rock Charles O, Gonzalez Frank J, Schuetz John D
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, Tennessee 38105, USA.
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Commun. 2015 Sep 29;6:8186. doi: 10.1038/ncomms9186.
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.
妊娠期肝内胆汁淤积症（ICP）与新生儿不良生存结局相关，据估计，全球范围内有0.4%至5%的妊娠会受到影响。我们在此表明，母体胆汁淤积（由于Abcb11缺乏）会导致所有后代在出生后24小时内因产生肺不张的肺缺氧而死亡，这重现了人类ICP的新生儿呼吸窘迫。Abcb11缺乏的母亲所生的新生儿肺胆汁酸水平升高，肺表面活性物质结构改变。在Abcb11缺乏的基础上，母体缺乏Nr1i2会显著降低母体血清胆汁酸浓度并提高新生儿存活率。我们确定肺胆汁酸是ICP新生儿肺表面活性物质结构破坏的关键因素。这些发现对新生儿呼吸衰竭具有重要意义，尤其是在孕期母体胆汁酸升高时，并突出了可能适合治疗干预以改善这种情况的潜在途径和靶点。
