HIF-1α Plays a Critical Role in the Gestational Sidestream Smoke-Induced Bronchopulmonary Dysplasia in Mice.
HIF-1α Plays a Critical Role in the Gestational Sidestream Smoke-Induced Bronchopulmonary Dysplasia in Mice.
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DOI：
10.1371/journal.pone.0137757
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sopori ML
中科院分区：
文献类型：
--
作者：
Singh SP;Chand HS;Gundavarapu S;Saeed AI;Langley RJ;Tesfaigzi Y;Mishra NC;Sopori ML
妊娠期吸烟可增加支气管肺发育不良（BPD）的风险，在小鼠中，妊娠期暴露于侧流香烟烟雾（SS）可诱导BPD样疾病，其特征为肺泡简化、血管生成受损和表面活性蛋白产生抑制。正常的胎儿发育发生在缺氧环境中，烟碱乙酰胆碱受体（nAChRs）调节控制细胞凋亡和血管生成的缺氧诱导因子（HIF）-1α。为了了解SS诱导的BPD，我们假设妊娠期SS通过HIF-1α影响肺泡发育。将妊娠BALB/c小鼠在整个妊娠期暴露于空气（对照）或SS中，并检查后代的7天大肺。GeolysSS增加肺泡和气道上皮细胞的凋亡。这种反应与肺泡体积增加、肺中促凋亡因子（FOXO 3 a、HIPK 2、p53、BIM、BIK和BAX）和抗血管生成因子（GAX）水平升高以及抗凋亡因子（Akt-PI 3 K、NF-κB、HIF-1α和Bcl-2）水平降低相关。虽然妊娠SS增加了含有促血管生成蛙皮素样肽的细胞，但它显著降低了肺中其受体GRPR的表达。SS对细胞凋亡的影响可被nAChR拮抗剂美加明减弱。吉西他滨诱导的BPD可能受nAChRs调节，并与HIF-1α下调、上皮细胞凋亡增加和肺泡体积增加相关。因此，在小鼠中，妊娠期间暴露于侧流烟草烟雾促进了可能通过nAChR/HIF-1α途径介导的BPD样疾病。
Smoking during pregnancy increases the risk of bronchopulmonary dysplasia (BPD) and, in mice, gestational exposure to sidestream cigarette smoke (SS) induces BPD-like condition characterized by alveolar simplification, impaired angiogenesis, and suppressed surfactant protein production. Normal fetal development occurs in a hypoxic environment and nicotinic acetylcholine receptors (nAChRs) regulate the hypoxia-inducible factor (HIF)-1α that controls apoptosis and angiogenesis. To understand SS-induced BPD, we hypothesized that gestational SS affected alveolar development through HIF-1α. Pregnant BALB/c mice were exposed to air (control) or SS throughout the gestational period and the 7-day-old lungs of the progeny were examined. Gestational SS increased apoptosis of alveolar and airway epithelial cells. This response was associated with increased alveolar volumes, higher levels of proapoptotic factors (FOXO3a, HIPK2, p53, BIM, BIK, and BAX) and the antiangiogenic factor (GAX), and lower levels of antiapoptotic factors (Akt-PI3K, NF-κB, HIF-1α, and Bcl-2) in the lung. Although gestational SS increased the cells containing the proangiogenic bombesin-like-peptide, it markedly decreased the expression of its receptor GRPR in the lung. The effects of SS on apoptosis were attenuated by the nAChR antagonist mecamylamine. Gestational SS-induced BPD is potentially regulated by nAChRs and associated with downregulation of HIF-1α, increased apoptosis of epithelial cells, and increased alveolar volumes. Thus, in mice, exposure to sidestream tobacco smoke during pregnancy promotes BPD-like condition that is potentially mediated through the nAChR/HIF-1α pathway.