Initial Suppression of Transforming Growth Factor-β Signaling and Loss of TGFBI Causes Early Alveolar Structural Defects Resulting in Bronchopulmonary Dysplasia
Initial Suppression of Transforming Growth Factor-β Signaling and Loss of TGFBI Causes Early Alveolar Structural Defects Resulting in Bronchopulmonary Dysplasia
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DOI：
10.1016/j.ajpath.2015.11.024
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发表时间：
2016-04-01
影响因子：
6
通讯作者：
Conway, Simon J.
中科院分区：
文献类型：
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作者：
Ahlfeld, Shawn K.;Wang, Jian;Conway, Simon J.
分离形态未成熟的小鼠肺的气体交换球囊需要调节转化生长因子(TGF)-β信号的时间、空间方向和剂量。我们发现，新生儿高氧最初急剧减少囊状转化生长因子-β信号，这与肺泡简化是一致的。然而，持续的高氧导致双相反应和随后的转化生长因子-β信号上调，最终导致支气管肺发育不良。值得注意的是，我们发现转化生长因子-β诱导的基质细胞蛋白(TGFBI)对高氧的反应类似地发生了双相改变。此外，基因消融显示TGFBI是正常肺泡结构和功能所必需的。虽然表型不是新生儿致死性的，但Tgfbi缺陷的肺在形态上是异常的。突变的间隔尖端发育不良，缺乏弹性蛋白阳性的尖端，表现出增殖减少，并含有异常持久的肺泡α-平滑肌肌动蛋白肌成纤维细胞。此外，Tgfbi缺陷的肺错误表达了转化生长因子-β反应的卵泡抑素和蛇床子素1，并暂时抑制了肌成纤维细胞血小板衍生生长因子α分化标记物。最后，尽管肺容量正常，但Tgfbi缺失的肺显示出弹性后坐力和气体交换效率降低。综上所述，这些数据表明，转化生长因子-β信号转导装置的最初抑制以及关键转化生长因子-β效应因子(如TGFBI)的丧失，是早期肺泡结构缺陷以及婴儿慢性肺部疾病患者常规观察到的长期功能缺陷的基础。这些研究强调了转化生长因子-β的复杂(通常是相互矛盾的)机制，并表明需要设计研究，将改变与提示支气管肺发育不良的表型改变的初始外观联系起来。
Septation of the gas-exchange saccules of the morphologically immature mouse lung requires regulated timing, spatial direction, and dosage of transforming growth factor (TGF)-beta signaling. We found that neonatal hyperoxia acutely initially diminished saccular TGF-beta signaling coincident with alveolar simplification. However, sustained hyperoxia resulted in a biphasic response and subsequent up regulation of TGF-beta signaling, ultimately resulting in bronchopulmonary dysplasia. Significantly, we found that the TGF-beta-induced matricellular protein (TGFBI) was similarly biphasically altered in response to hyperoxia. Moreover, genetic ablation revealed that TGFBI was required for normal alveolar structure and function. Although the phenotype was not neonatal lethal, Tgfbi-deficient Lungs were morphologically abnormal. Mutant septal tips were stunted, lacked elastin-positive tips, exhibited reduced proliferation, and contained abnormally persistent alveolar alpha-smooth muscle actin myofibroblasts. In addition, Tgfbi-deficient lungs misexpressed TGF-beta-responsive follistatin and serpine 1, and transiently suppressed myofibroblast platelet-derived growth factor alpha differentiation marker. Finally, despite normal lung volume, Tgfbi-null lungs displayed diminished elastic recoil and gas exchange efficiency. Combined, these data demonstrate that initial suppression of the TGF-beta signaling apparatus, as well as Loss of key TGF-beta effectors (like TGFBI), underlies early alveolar structural defects, as well as long-lasting functional deficits routinely observed in chronic lung disease of infancy patients. These studies underline the complex (and often contradictory) rote of TGF-beta and indicate a need to design studies to associate alterations with initial appearance of phenotypical changes suggestive of bronchopulmonary dysplasia.