Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation.
Bone Morphogenetic Protein 9 Protects against Neonatal Hyperoxia-Induced Impairment of Alveolarization and Pulmonary Inflammation.
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骨形态发生蛋白9可预防新生儿高氧引起的肺泡化和肺部炎症损伤。
DOI：
10.3389/fphys.2017.00486
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发表时间：
2017
影响因子：
4
通讯作者：
Wagenaar GTM
中科院分区：
文献类型：
--
作者：
Chen X;Orriols M;Walther FJ;Laghmani EH;Hoogeboom AM;Hogen-Esch ACB;Hiemstra PS;Folkerts G;Goumans MTH;Ten Dijke P;Morrell NW;Wagenaar GTM
目的：支气管肺发育不良（BPD）早产儿缺乏有效的治疗。我们假设骨形态发生蛋白9（BMP 9），一种TGF-β家族的配体，与激活素受体样激酶1（ALK 1）-BMP受体2型（BMPR 2）受体复合物结合，可能是BPD的一种新的治疗选择。因此，我们研究了BMP 9对新生Wistar大鼠高氧诱导的BPD的心肺作用。方法：Wistar大鼠仔鼠出生后立即暴露于100%氧气中10天。从第2天开始，大鼠幼仔通过皮下注射接受BMP 9（2.5 μg/kg，每天两次）或0.9%NaCl。通过形态测量分析和细胞因子产生研究了BMP 9对异常肺泡发育、肺部炎症和纤维化以及右心室肥大（RVH）的有益作用。此外，在实验性BPD的发展过程中，研究了BMP 9及其受体复合物：ALK 1、BMPR 2和Endoglin以及ALK 1下游靶跨膜蛋白100（TMEM 100）的差异mRNA表达。在人内皮和上皮细胞培养物中研究了BMP 9受体复合物和TMEM 100的表达，并在内皮细胞培养物中研究了BMP 9对炎性细胞因子产生和TMEM 100表达的影响。结果如下：ALK 1，ALK 2，BMPRII，TMEM 100和Endoglin在实验性BPD中差异表达，表明BMP 9依赖性信号传导在（实验性）BPD发展中的作用。TMEM 100在血管壁表达，在小动脉中显示弹性蛋白样表达模式。高氧暴露后TMEM 100 mRNA和蛋白表达降低。用BMP 9治疗高氧诱导的实验性BPD大鼠幼崽可减少肺泡扩大、肺间隔厚度和纤维化，并预防炎症，但不能减弱血管重塑和RVH。BMP 9的抗炎作用在体外得到证实。在人内皮细胞培养物中观察到ALK 1、BMPR 2和TMEM 100的最高表达。用BMP 9刺激人内皮细胞培养物降低了它们的促炎细胞因子应答并诱导肺动脉内皮细胞中的TMEM 100表达。结论：BMP 9通过改善异常肺泡发育、炎症和纤维化来保护新生儿免受高氧诱导的BPD，证明了其对患有严重BPD的早产儿的治疗潜力。
Aim: Effective treatment of premature infants with bronchopulmonary dysplasia (BPD) is lacking. We hypothesize that bone morphogenetic protein 9 (BMP9), a ligand of the TGF-β family that binds to the activin receptor-like kinase 1 (ALK1)-BMP receptor type 2 (BMPR2) receptor complex, may be a novel therapeutic option for BPD. Therefore, we investigated the cardiopulmonary effects of BMP9 in neonatal Wistar rats with hyperoxia-induced BPD. Methods: Directly after birth Wistar rat pups were exposed to 100% oxygen for 10 days. From day 2 rat pups received BMP9 (2.5 μg/kg, twice a day) or 0.9% NaCl by subcutaneous injection. Beneficial effects of BMP9 on aberrant alveolar development, lung inflammation and fibrosis, and right ventricular hypertrophy (RVH) were investigated by morphometric analysis and cytokine production. In addition, differential mRNA expression of BMP9 and its receptor complex: ALK1, BMPR2, and Endoglin, and of the ALK1 downstream target transmembrane protein 100 (TMEM100) were studied during the development of experimental BPD. Expression of the BMP9 receptor complex and TMEM100 was studied in human endothelial and epithelial cell cultures and the effect of BMP9 on inflammatory cytokine production and TMEM100 expression was studied in endothelial cell cultures. Results: ALK1, ALK2, BMPRII, TMEM100, and Endoglin were differentially expressed in experimental BPD, suggesting a role for BMP9-dependent signaling in the development of (experimental) BPD. TMEM100 was expressed in the wall of blood vessels, showing an elastin-like expression pattern in arterioles. Expression of TMEM100 mRNA and protein was decreased after exposure to hyperoxia. BMP9 treatment of rat pups with hyperoxia-induced experimental BPD reduced alveolar enlargement, lung septal thickness and fibrosis, and prevented inflammation, but did not attenuate vascular remodeling and RVH. The anti-inflammatory effect of BMP9 was confirmed in vitro. Highest expression of ALK1, BMPR2, and TMEM100 was observed in human endothelial cell cultures. Stimulation of human endothelial cell cultures with BMP9 reduced their pro-inflammatory cytokine response and induced TMEM100 expression in pulmonary arterial endothelial cells. Conclusion: BMP9 protects against neonatal hyperoxia-induced BPD by improving aberrant alveolar development, inflammation and fibrosis, demonstrating its therapeutic potential for premature infants with severe BPD.
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影响因子：
6
作者：
Gauldie, J;Galt, T;Warburton, D
通讯作者：
Warburton, D
DOI：
10.1152/ajplung.00050.2006
发表时间：
2007-02-01
影响因子：
4.9
作者：
Alejandre-Alcazar, Miguel A.;Kwapiszewska, Grazyna;Morty, Rory E.
通讯作者：
Morty, Rory E.
DOI：
10.1002/bdra.23220
发表时间：
2014-03-01
影响因子：
--
作者：
Bhandari, Vineet
通讯作者：
Bhandari, Vineet
DOI：
10.1152/ajplung.00270.2010
发表时间：
2011-03-01
影响因子：
4.9
作者：
Chen, Shaoyi;Rong, Min;Wu, Shu
通讯作者：
Wu, Shu
影响因子：
5.1
作者：
Kang, Q;Sun, MH;He, TC
通讯作者：
He, TC