Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.
Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury.
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新生儿肺损伤作为高氧（HO）治疗和呼吸机护理的结果有助于支气管肺发育不良（BPD）的发展。交联胶原的关键酶赖氨酸氧化酶（LOX）的表达和活性增加与人BPD中鞘氨酸激酶1 （SPHK1）的增加有关。因此，我们仔细研究了BPD中LOX和SPHK1之间的联系。采用免疫组化和Halo法测定人BPD肺组织中SPHK1和LOX酶的表达。体内研究是基于Sphk1−/−和匹配的野生型（WT）新生小鼠，在接受Sphk1抑制剂PF543治疗的同时暴露于HO。体外机制研究使用人肺微血管内皮细胞（HLMVECs）。BPD患者肺组织中SPHK1和LOX表达均升高。BPD患者的气管吸入物LOX增加，与鞘氨醇-1-磷酸（S1P）水平相关。在Sphk1−/−和pf543处理的WT小鼠中，ho诱导的肺LOX增加减弱，并伴有胶原染色减少（天狼星红）。PF543降低了HO后hlmves支气管肺泡灌洗液和上清液中的LOX活性。芯片分析显示STAT3是LOX的潜在转录调控因子。在hlmvec中，HO后，ChIP检测证实STAT3与LOX启动子的结合增加。抑制SPHK1可降低STAT3的磷酸化。抗SPNS2、S1P受体1 （S1P1）和STAT3的S1P和siRNA抗体可降低LOX的表达。ho诱导的SPHK1/S1P信号轴通过SPNS2、S1P1和STAT3在肺内皮中对LOX表达的转录调控中起关键作用。
Neonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD. The enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs). Both SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression. HO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.
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影响因子：
4.6
作者：
Aumiller V;Strobel B;Romeike M;Schuler M;Stierstorfer BE;Kreuz S
通讯作者：
Kreuz S
DOI：
10.1152/ajplung.00176.2014
发表时间：
2015-08-15
影响因子：
4.9
作者：
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通讯作者：
Berkelhamer, Sara K.
影响因子：
7.4
作者：
Berkelhamer, Sara K.;Kim, Gina A.;Radder, Josiah E.;Wedgwood, Stephen;Czech, Lyubov;Steinhorn, Robin H.;Schumacker, Paul T.
通讯作者：
Schumacker, Paul T.
影响因子：
5.6
作者：
Huang, Long Shuang;Sudhadevi, Tara;Natarajan, Viswanathan
通讯作者：
Natarajan, Viswanathan
影响因子：
3.1
作者：
Hendricks-Munoz, Karen D.;Xu, Jie;Voynow, Judith A.
通讯作者：
Voynow, Judith A.