Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema
Abnormal mouse lung alveolarization caused by Smad3 deficiency is a developmental antecedent of centrilobular emphysema
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DOI：
10.1152/ajplung.00298.2004
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发表时间：
2005-04-01
影响因子：
4.9
通讯作者：
Shi, W
中科院分区：
文献类型：
--
作者：
Chen, H;Sun, JP;Shi, W
转化生长因子-β (TGF-β) 信号在肺发育和重塑过程中发挥着重要的调节作用。 Smad3 是从细胞膜到细胞核的 TGF-β 途径中的主要下游信号转导器。在 Smad3 缺失突变小鼠中，我们观察到从出生后第 7 天到第 28 天肺泡化迟缓，随后从第 28 天开始出现小叶中心性肺气肿（通过形态测量分析确定）。除了形态学变化外，与野生型对照相比，出生后第 7 天至第 28 天，Smad3 敲除小鼠的外周肺细胞增殖有所减少。从出生后第 28 天到成年期，Smad3 敲除小鼠的肺中原弹性蛋白的 mRNA 表达也显着降低。此外，在出生后第28天，当小叶中心性肺气肿病理刚刚开始出现时，在Smad3敲除小鼠的肺组织和支气管肺泡灌洗液中检测到基质金属蛋白酶-9蛋白表达和活性增加。因此，这些结果表明，Smad3不仅对新生儿肺泡化具有积极的调节作用，而且还可能对日后小叶中心性肺气肿的发生发挥保护作用。
Transforming growth factor-beta (TGF-beta) signaling plays an important regulatory role during lung development and remodeling. Smad3 is a major downstream signal transducer in the TGF-beta pathway from the cell membrane to the nucleus. In Smad3 null mutant mice, we have observed retarded lung alveolarization from postnatal day 7 to day 28, and subsequently centrilobular emphysema starting from day 28, as determined by morphometric analysis. In addition to the morphological changes, peripheral lung cell proliferation in Smad3 knockout mice was reduced compared with the wild-type control between postnatal days 7 and 28. Expression of tropoelastin at the mRNA level was also dramatically decreased in Smad3 knockout lungs from postnatal day 28 through adulthood. Furthermore, increased matrix metalloproteinase- 9 protein expression and activity were detected in the Smad3 knockout mouse lung tissue and the bronchoalveolar lavage fluid at postnatal day 28 when the centrilobular emphysema pathology was just beginning to appear. Therefore, these results indicate that Smad3 not only has a positive regulatory impact on neonatal lung alveolarization but also potentially plays a protective role against the occurrence of centrilobular emphysema later on in life.