Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia
Hyperoxia modulates TGF-β/BMP signaling in a mouse model of bronchopulmonary dysplasia
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DOI：
10.1152/ajplung.00050.2006
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发表时间：
2007-02-01
影响因子：
4.9
通讯作者：
Morty, Rory E.
中科院分区：
文献类型：
--
作者：
Alejandre-Alcazar, Miguel A.;Kwapiszewska, Grazyna;Morty, Rory E.
需要氧疗的早产儿通常会发展为支气管肺发育不良(BPD)，这是一种以明显的肺泡发育不全为特征的衰弱疾病。高氧损伤被认为扰乱了引导肺发育的关键信号通路，导致BPD。在出生后第1天至第28天，我们研究了常压高氧对新生C57BL/6J小鼠暴露于21%或85%O-2环境中转化生长因子-β和骨形态发生蛋白信号的影响。暴露于85%O-2的幼鼠的生长和呼吸顺应性显著受损，这些幼鼠还表现出明显的肺泡化停止，并伴有受体(ALK-1、ALK-3、ALK-6和转化生长因子-βII受体)和Smad(Smads 1、3和4)蛋白的异常表达和定位。在85%O-2暴露的幼鼠肺、MLE-12小鼠肺上皮细胞、NIH/3T3和85%O-2培养的原代肺成纤维细胞中，转化生长因子-β信号被增强，而BMP信号被抑制。85%O-2暴露后，原代肺泡II型细胞对转化生长因子-β诱导的细胞凋亡更敏感，而原代肺动脉平滑肌细胞不受影响。原代肺成纤维细胞暴露于85%O-2可显著增加转化生长因子-β刺激的I型胶原α(1)亚单位(Iα(1))、金属蛋白酶组织抑制因子-1、原弹性蛋白和张力蛋白-C的产生。这些数据表明，高氧显著影响肺中的转化生长因子-β/骨形态发生蛋白信号，包括肺间隔中心的过程，因此，肺泡化。这些途径对遗传和药物操纵的适应性可能为BPD的管理提供替代途径。
Prematurely born infants who require oxygen therapy often develop bronchopulmonary dysplasia (BPD), a debilitating disorder characterized by pronounced alveolar hypoplasia. Hyperoxic injury is believed to disrupt critical signaling pathways that direct lung development, causing BPD. We investigated the effects of normobaric hyperoxia on transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) signaling in neonatal C57BL/6J mice exposed to 21% or 85% O-2 between postnatal days P1 and P28. Growth and respiratory compliance were significantly impaired in pups exposed to 85% O-2, and these pups also exhibited a pronounced arrest of alveolarization, accompanied by dysregulated expression and localization of both receptor (ALK-1, ALK-3, ALK-6, and the TGF-beta type II receptor) and Smad (Smads 1, 3, and 4) proteins. TGF-beta signaling was potentiated, whereas BMP signaling was impaired both in the lungs of pups exposed to 85% O-2 as well as in MLE-12 mouse lung epithelial cells and NIH/3T3 and primary lung fibroblasts cultured in 85% O-2. After exposure to 85% O-2, primary alveolar type II cells were more susceptible to TGF-beta-induced apoptosis, whereas primary pulmonary artery smooth muscle cells were unaffected. Exposure of primary lung fibroblasts to 85% O-2 significantly enhanced the TGF-beta-stimulated production of the alpha(1) subunit of type I collagen (I alpha(1)), tissue inhibitor of metalloproteinase-1, tropoelastin, and tenascin-C. These data demonstrated that hyperoxia significantly affects TGF-beta/BMP signaling in the lung, including processes central to septation and, hence, alveolarization. The amenability of these pathways to genetic and pharmacological manipulation may provide alternative avenues for the management of BPD.