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Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury.

肝雌激素硫转移酶使小鼠对失血性休克诱导的急性肺损伤远增敏感。

  • 影响因子:3.62
  • DOI:10.1210/endocr/bqz031
  • 作者列表:"Xie Y","Barbosa ACS","Xu M","Oberly PJ","Ren S","Gibbs RB","Poloyac SM","Song WC","Fan J","Xie W
  • 发表时间:2020-01-01
Abstract

:Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The estrogen sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.

摘要

失血性休克 (HS) 是一种潜在的危及生命的疾病,可能导致多个器官的损伤,包括肺。雌激素磺基转移酶 (EST,或 SULT1E1) 是一种磺化和灭活雌激素的结合酶。在本报告中,我们发现在接受 HS 和复苏的雌性小鼠的肝脏中明显诱导了 Est 的表达,而在肺中没有诱导。Est 的遗传消融或药理学抑制有效地保护雌性小鼠免受 HS 诱导的急性肺损伤 (ALI),包括间质水肿、中性粒细胞动员和浸润以及炎症。Est 消融或抑制的脉冲保护作用具有性别特异性,因为 HS 诱导的 ALI 在雄性 Est-/-小鼠中不受影响。机制上,雌性 Est-/-小鼠的 pulmonoprotective 表型伴随着肺和循环中雌激素水平的增加,肺部炎症减轻, 抑制骨髓中性粒细胞动员和中性粒细胞浸润到肺,而卵巢切除术后肺脏保护作用消失,提示保护作用是雌激素依赖性的。Est 消融的脉冲保护作用也是组织特异性的,因为 Est 的丢失对 HS 诱导的肝损伤几乎没有影响。此外,在全球 EST-/-小鼠的肝脏中转基因重建人 Est 消除了脉冲保护作用,表明它是肝脏中的 EST 使小鼠对 HS 诱导的 ALI 敏感。总之,我们的结果揭示了 EST 在 HS 诱导的 ALI 中的性别和组织特异性作用。药理学抑制 EST 可能是管理 HS 诱导的 ALI 的有效方法。

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DOI:10.1016/j.taap.2019.114847
作者列表:["Bernstein DM","Toth B","Rogers RA","Kling DE","Kunzendorf P","Phillips JI","Ernst H"]

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DOI:10.1042/BST20191010
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