Kang Hye-Ryun, Lee Chun Geun, Homer Robert J, Elias Jack A
Section of Pulmonary and Critical Care Medicine and 2Department of Pathology, Yale University School of Medicine, New Haven, CT 06519, USA.
J Exp Med. 2007 May 14;204(5):1083-93. doi: 10.1084/jem.20061273. Epub 2007 May 7.
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 beta1 integrins, are stimulated by transforming growth factor (TGF)-beta(1) in the murine lung. They also demonstrate that SEMA 7A plays a critical role in TGF-beta(1)-induced fibrosis, myofibroblast hyperplasia, alveolar remodeling, and apoptosis. TGF-beta(1) 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-beta(1) 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-beta(1)-induced fibrosis. These observations demonstrate that SEMA 7A and its receptors are induced by TGF-beta(1) and that SEMA 7A plays a central role in a PI3K/PKB/AKT-dependent pathway that contributes to TGF-beta(1)-induced fibrosis and remodeling. They also demonstrate that the effects of SEMA 7A are not specific for transgenic TGF-beta(1), highlighting the importance of these findings for other fibrotic stimuli.
信号素（SEMA）7A调节神经元和免疫功能。在这些研究中，我们检验了SEMA 7A也是组织重塑关键调节因子的假说。这些研究表明，在小鼠肺中，转化生长因子（TGF）-β1可刺激SEMA 7A及其受体神经丛蛋白C1和β1整合素。研究还表明，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通过一种很大程度上不依赖Smad 3的机制刺激SEMA 7A，并通过不依赖Smad 2/3和依赖SEMA 7A的机制刺激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受体成分、蛋白酶、抗蛋白酶和凋亡调节因子。SEMA 7A在博来霉素诱导的肺纤维化发病机制中也起重要作用。TGF-β 和博来霉素还通过依赖SEMA 7A的机制激活磷脂酰肌醇3激酶（PI3K）和蛋白激酶B（PKB）/AKT，抑制PKB/AKT可减少TGF-β1诱导的纤维化。这些观察结果表明，TGF-β1可诱导SEMA 7A及其受体，且SEMA 7A在PI3K/PKB/AKT依赖的途径中起核心作用，该途径导致TGF-β1诱导的纤维化和重塑。研究还表明，SEMA 7A的作用并非转基因TGF-β1所特有，这突出了这些发现对其他纤维化刺激因素的重要性。
