Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis.
Semaphorin 7A plays a critical role in TGF-beta1-induced pulmonary fibrosis.
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DOI：
10.1084/jem.20061273
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发表时间：
2007-05-14
期刊：
影响因子：
--
通讯作者：
Elias JA
中科院分区：
文献类型：
--
作者：
Kang HR;Lee CG;Homer RJ;Elias JA
Semaphorin（SEMA）7A调节神经元和免疫功能。在这些研究中，我们测试了SEMA 7A也是组织重塑的关键调节剂的假设。这些研究表明，SEMA 7A及其受体丛蛋白C1和β1整联蛋白在鼠肺中受到转化生长因子（TGF）-β1的刺激。他们还证明SEMA 7A在TGF-β1诱导的纤维化、肌成纤维细胞增生、肺泡重塑和细胞凋亡中起关键作用。TGF-β1主要通过Smad 3非依赖性机制刺激SEMA 7A，并通过Smad 2/3非依赖性和SEMA 7A依赖性机制刺激SEMA 7A受体、基质蛋白、CCN蛋白、成纤维细胞生长因子2、白细胞介素13受体组分、蛋白酶、抗蛋白酶和凋亡调节因子。SEMA 7A在博莱霉素诱导的肺纤维化的发病机制中也起重要作用。TGF-β1和博莱霉素还通过SEMA 7A依赖性机制激活磷脂酰肌醇3-激酶（PI 3 K）和蛋白激酶B（PKB）/AKT，并且PKB/AKT抑制剂减轻TGF-β1诱导的纤维化。这些观察结果表明，SEMA 7A及其受体是由TGF-β1诱导的，并且SEMA 7A在PI 3 K/PKB/AKT依赖性途径中发挥核心作用，该途径有助于TGF-β1诱导的纤维化和重塑。他们还证明，SEMA 7A的作用对转基因TGF-β1并不特异，这突出了这些发现对其他纤维化刺激的重要性。
Semaphorin (SEMA) 7A regulates neuronal and immune function. In these studies, we tested the hypothesis that SEMA 7A is also a critical regulator of tissue remodeling. These studies demonstrate that SEMA 7A and its receptors, plexin C1 and β1 integrins, are stimulated by transforming growth factor (TGF)-β1 in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-β1–induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-β1 stimulated SEMA 7A via a largely Smad 3–independent mechanism and stimulated SEMA 7A receptors, matrix proteins, CCN proteins, fibroblast growth factor 2, interleukin 13 receptor components, proteases, antiprotease, and apoptosis regulators via Smad 2/3–independent and SEMA 7A–dependent mechanisms. SEMA 7A also played an important role in the pathogenesis of bleomycin-induced pulmonary fibrosis. TGF-β1 and bleomycin also activated phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB)/AKT via SEMA 7A–dependent mechanisms, and PKB/AKT inhibition diminished TGF-β1–induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-β1 and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-β1–induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-β1, highlighting the importance of these findings for other fibrotic stimuli.
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