Hyperoxia-induced neonatal rat lung injury involves activation of TGF-β and Wnt signaling and is protected by rosiglitazone
Hyperoxia-induced neonatal rat lung injury involves activation of TGF-β and Wnt signaling and is protected by rosiglitazone
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DOI：
10.1152/ajplung.90392.2008
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发表时间：
2009-06-01
影响因子：
4.9
通讯作者：
Rehan, Virender K.
中科院分区：
文献类型：
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作者：
Dasgupta, Chiranjib;Sakurai, Reiko;Rehan, Virender K.
Dasgupta C，Sakurai R，Wang Y，Guo P，Ambalavanan N，Torday JS，Rehan VK.高氧诱导的新生大鼠肺损伤涉及TGF-β和Wnt信号的激活，并受到罗格列酮的保护。美国生理学杂志肺细胞分子生理学296：L1031-L1041，2009年。首次发表于2009年3月20日; doi：10.1152/ajplung.90392.2008。尽管技术和治疗取得了巨大进步，但支气管肺发育不良（BPD）仍然是极低出生体重儿呼吸系统发病的主要原因，并且没有有效的预防和/或治疗选择。我们以前报道过罗格列酮（RGZ）可以预防高氧诱导的新生大鼠肺损伤。在这里，我们描述了1）无翅/Int（Wnt）和转化生长因子（TGF）-β信号传导的扰动，以及2）新生大鼠连续7天体内高氧暴露后肺形态的结构畸变。我们还测试了是否与RGZ，伴随着高氧治疗的新生幼崽，可以防止这种畸变。我们的研究表明，高氧导致Wnt信号蛋白标记淋巴增强因子1（Lef-1）和β-连环蛋白和TGF-β通路转导蛋白磷酸化Smad 3和Smad 7蛋白在整个大鼠肺提取物的显着上调。这些变化还伴随着肌生成标记蛋白α-平滑肌肌动蛋白（α-SMA）和钙调蛋白的上调，但脂肪生成标记过氧化物酶体增殖物激活受体-γ（PPAR γ）表达的显着下调。这些分子扰动与肺泡间隔厚度、径向肺泡计数和高氧暴露肺中较大肺泡的减少相关。这些高氧诱导的分子和形态学变化被全身给予RGZ预防，肺切片接近正常。这是体内高氧诱导肺中Wnt和TGF-β信号转导途径激活以及RGZ几乎完全预防的第一个证据。高氧诱导的肺泡发育停滞是BPD的标志，沿着这些分子变化强烈暗示这些蛋白质在高氧诱导的肺损伤中。因此，给予PPAR γ激动剂可能是减轻高氧诱导的肺损伤和随后的BPD的潜在策略。
Dasgupta C, Sakurai R, Wang Y, Guo P, Ambalavanan N, Torday JS, Rehan VK. Hyperoxia-induced neonatal rat lung injury involves activation of TGF-beta and Wnt signaling and is protected by rosiglitazone. Am J Physiol Lung Cell Mol Physiol 296: L1031-L1041, 2009. First published March 20, 2009; doi: 10.1152/ajplung.90392.2008.-Despite tremendous technological and therapeutic advances, bronchopulmonary dysplasia (BPD) remains a leading cause of respiratory morbidity in very low birth weight infants, and there are no effective preventive and/or therapeutic options. We have previously reported that hyperoxia-induced neonatal rat lung injury might be prevented by rosiglitazone (RGZ). Here, we characterize 1) perturbations in wingless/Int (Wnt) and transforming growth factor (TGF)-beta signaling, and 2) structural aberrations in lung morphology following 7-day continuous in vivo hyperoxia exposure to neonatal rats. We also tested whether treatment of neonatal pups with RGZ, concomitant to hyperoxia, could prevent such aberrations. Our study revealed that hyperoxia caused significant upregulation of Wnt signaling protein markers lymphoid enhancer factor 1 (Lef-1) and beta-catenin and TGF-beta pathway transducers phosphorylated Smad3 and Smad7 proteins in whole rat lung extracts. These changes were also accompanied by upregulation of myogenic marker proteins alpha-smooth muscle actin (alpha-SMA) and calponin but significant downregulation of the lipogenic marker peroxisome proliferator-activated receptor-gamma (PPAR gamma) expression. These molecular perturbations were associated with reduction in alveolar septal thickness, radial alveolar count, and larger alveoli in the hyperoxia-exposed lung. These hyperoxia-induced molecular and morphological changes were prevented by systemic administration of RGZ, with lung sections appearing near normal. This is the first evidence that in vivo hyperoxia induces activation of both Wnt and TGF-beta signal transduction pathways in lung and of its near complete prevention by RGZ. Hyperoxia-induced arrest in alveolar development, a hallmark of BPD, along with these molecular changes strongly implicates these proteins in hyperoxia-induced lung injury. Administration of PPAR gamma agonists may thus be a potential strategy to attenuate hyperoxia-induced lung injury and subsequent BPD.