ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation
ADAMTS18 Deficiency Leads to Pulmonary Hypoplasia and Bronchial Microfibril Accumulation
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ADAMTS18 缺乏导致肺发育不全和支气管微纤维积聚
DOI：
10.1016/j.isci.2020.101472
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发表时间：
2020-09-25
期刊：
影响因子：
5.8
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Lu, Tiantian;Lin, Xiaotian;Zhang, Wei
ADAMTS（具有血小板反应蛋白基序的去整合素和金属蛋白酶）是分泌的金属蛋白酶，其在细胞外基质（ECM）的组装和降解中起主要作用。在这项研究中，我们表明，ADAMTS 18，所产生的远端气道上皮细胞和肺尖间充质细胞在早期胚胎阶段，作为肺发育的形态。ADAMTS 18缺乏导致支气管数量和长度减少，肺尖倾斜和肺泡扩张。这些发育缺陷使脂多糖诱导的急性肺损伤和博莱霉素诱导的成年Adamts 18缺陷小鼠肺纤维化恶化。ADAMTS 18缺陷还导致原纤维蛋白1和原纤维蛋白2水平升高、支气管微纤维积聚、粘着斑激酶信号传导降低和F-肌动蛋白组织破坏。我们的研究结果表明，ADAMTS 18介导的ECM稳态是气道分支形态发生的关键。
ADAMTSs (a disintegrin and metalloproteinase with thrombospondin motifs) are secreted metalloproteinases that play a major role in the assembly and degradation of the extracellular matrix (ECM). In this study, we show that ADAMTS18, produced by the epithelial cells of distal airways and mesenchymal cells in lung apex at early embryonic stages, serves as a morphogen in lung development. ADAMTS18 deficiency leads to reduced number and length of bronchi, tipped lung apexes, and dilated alveoli. These developmental defects worsen lipopolysaccharide-induced acute lung injury and bleomycin-induced lung fibrosis in adult Adamts18-deficient mice. ADAMTS18 deficiency also causes increased levels of fibrillin1 and fibrillin2, bronchial microfibril accumulation, decreased focal adhesion kinase signaling, and disruption of F-actin organization. Our findings indicate that ECM homeostasis mediated by ADAMTS18 is pivotal in airway branching morphogenesis.