Sildenafil Alleviates Bronchopulmonary Dysplasia in Neonatal Rats by Activating the Hypoxia-Inducible Factor Signaling Pathway
Sildenafil Alleviates Bronchopulmonary Dysplasia in Neonatal Rats by Activating the Hypoxia-Inducible Factor Signaling Pathway
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DOI：
10.1165/rcmb.2012-0043oc
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发表时间：
2013-01-01
影响因子：
6.4
通讯作者：
Chun, Yang-Sook
中科院分区：
文献类型：
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作者：
Park, Hyoung-Sook;Park, Jong-Wan;Chun, Yang-Sook
支气管肺发育不良（BPD）是接受氧疗的早产儿发病的主要原因。目前，西地那非正在接受临床检验，以改善 BPD 患者的肺功能。根据西地那非的药理作用，肺组织中环鸟苷 3',5'-单磷酸 (cGMP) 的升高被认为是其有益作用的基础，但这种机制在分子水平上尚不清楚。在这里，我们研究了西地那非帮助肺部系统适应高氧应激的可能性。为了诱导 BPD，胎鼠在分娩前暴露于 LPS，新生儿暴露于高氧环境，然后腹腔注射西地那非。暴露于高氧的大鼠的肺泡化受到损害，而西地那非的肺泡化显着恢复。免疫组织化学检查显示，西地那非有效增加了肺组织中的血管分布。此外，氧传感器缺氧诱导因子（HIF）-1/2α和血管生成因子血管内皮生长因子（VEGF）在西地那非治疗大鼠的肺部高度表达。在人小气道上皮细胞中，HIF-1/2α及其下游基因（包括VEGF）被证实在蛋白质和mRNA水平上被西地那非诱导。从机制上讲，西地那非治疗后，由于 5 型磷酸二酯酶的干扰，气道细胞中的 cGMP 积累，随后 cGMP 通过刺激磷酸肌醇 3-激酶 (PI3K)-v-akt 鼠胸腺瘤病毒癌基因同源物 1 (AKT)-哺乳动物雷帕霉素靶点 (mTOR) 途径激活 HIF 介导的缺氧信号。这项研究让我们更好地了解西地那非的作用方式，并表明 HIF 可以成为治疗 BPD 患者的潜在靶点。
Bronchopulmonary dysplasia (BPD) is a major cause of morbidity in premature infants receiving oxygen therapy. Currently, sildenafil is being examined clinically to improve pulmonary function in patients with BPD. Based on the pharmacological action of sildenafil, the elevation of cyclic guanosine 3',5'-monophosphate (cGMP) in lung tissue is considered to underlie its beneficial effects, but this mechanism is not understood at the molecular level. Here, we examined the possibility that sildenafil helps the pulmonary system adapt to hyperoxic stress. To induce BPD, fetal rats were exposed to LPS before delivery, and neonates were exposed to hyperoxia, followed by intraperitoneal injections of sildenafil. Alveolarization was impaired in rats exposed to hyperoxia, and alveolarization significantly recovered with sildenafil. An immunohistochemical examination revealed that sildenafil effectively increased vascular distribution in lung tissue. Furthermore, the oxygen sensor hypoxia-inducible factor (HIF)-1/2 alpha and the angiogenic factor vascular endothelial growth factor (VEGF) were highly expressed in the lungs of sildenafil-treated rats. In human small-airway epithelial cells, HIF-1/2 alpha and its downstream genes, including VEGF, were confirmed to be induced by sildenafil at both the protein and mRNA levels. Mechanistically, cGMP in airway cells accumulated after sildenafil treatment because of interfering phosphodiesterase Type 5, and subsequently cGMP activated HIF-mediated hypoxic signaling by stimulating the phosphoinositide 3-kinase (PI3K)-v-akt murine thymoma viral oncogene homolog 1 (AKT)-mammalian target of rapamycin (mTOR) pathway. This study provides a better understanding about the mode of action for sildenafil, and suggests that HIF can be a potential target for treating patients with BPD.