Smad3 null mice develop airspace enlargement and are resistant to TGF-β-mediated pulmonary fibrosis
Smad3 null mice develop airspace enlargement and are resistant to TGF-β-mediated pulmonary fibrosis
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DOI：
10.4049/jimmunol.173.3.2099
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Gauldie, J
中科院分区：
文献类型：
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作者：
Bonniaud, P;Kolb, M;Gauldie, J
转化生长因子-β 1在肺纤维化的发病机制中起关键作用，通过一系列细胞内信号分子（包括Smad 2和Smad 3）介导细胞外基质（ECM）基因表达。我们发现Smad 3基因敲除小鼠（KO）的肺泡空间大小逐渐增加，与肺中基质金属蛋白酶（MMP-9和MMP-12）的自发存在有关。此外，使用腺病毒载体介导的基因转移，在肺中短暂过表达活性TGF-β 1，导致野生型小鼠进行性肺纤维化，而Smad 3 KO小鼠肺中没有纤维化观察到长达28天。TGF-β 1给药后4天，在野生型肺中检测到显著较高水平的基质成分（前胶原3A 1，结缔组织生长因子）和抗蛋白酶（纤溶酶原激活物抑制剂-1，金属蛋白酶组织抑制剂-1），而在KO肺中未观察到此类变化。这些数据表明Smad 3途径在ECM代谢中的关键作用。该途径的基础活性是维持肺泡完整性和ECM稳态所必需的，但通过该途径的过度信号传导导致以抑制降解和增强ECM沉积为特征的纤维化。Smad 3通路参与介导组织破坏（缺乏修复）和纤维化（过度修复）的致病机制。
Transforming growth factor-beta1 plays a key role in the pathogenesis of pulmonary fibrosis, mediating extracellular matrix (ECM) gene expression through a series of intracellular signaling molecules, including Smad2 and Smad3. We show that Smad3 null mice (knockout (KO)) develop progressive age-related increases in the size of alveolar spaces, associated with high spontaneous presence of matrix metalloproteinases (MMP-9 and MMP-12) in the lung. Moreover, transient overexpression of active TGF-beta1 in lungs, using adenoviral vector-mediated gene transfer, resulted in progressive pulmonary fibrosis in wild-type mice, whereas no fibrosis was seen in the lungs of Smad3 KO mice up to 28 days. Significantly higher levels of matrix components (procollagen 3A1, connective tissue growth factor) and antiproteinases (plasminogen activator inhibitor-1, tissue inhibitor of metalloproteinase-1) were detected in wild-type lungs 4 days after TGF-beta1 administration, while no such changes were seen in KO lungs. These data suggest a pivotal role of the Smad3 pathway in ECM metabolism. Basal activity of the pathway is required to maintain alveolar integrity and ECM homeostasis, but excessive signaling through the pathway results in fibrosis characterized by inhibited degradation and enhanced ECM deposition. The Smad3 pathway is involved in pathogenic mechanisms mediating tissue destruction (lack of repair) and fibrogenesis (excessive repair).