Tsoyi Konstantin, Chu Sarah G, Patino-Jaramillo Nasly G, Wilder Julie, Villalba Julian, Doyle-Eisele Melanie, McDonald Jacob, Liu Xiaoli, El-Chemaly Souheil, Perrella Mark A, Rosas Ivan O
1 Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; and.
2 Pulmonary Fibrosis Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
Am J Respir Cell Mol Biol. 2018 Feb;58(2):208-215. doi: 10.1165/rcmb.2017-0088OC.
Radiation-induced pulmonary fibrosis is a severe complication of patients treated with thoracic irradiation. We have previously shown that syndecan-2 reduces fibrosis by exerting alveolar epithelial cytoprotective effects. Here, we investigate whether syndecan-2 attenuates radiation-induced pulmonary fibrosis by inhibiting fibroblast activation. C57BL/6 wild-type mice and transgenic mice that overexpress human syndecan-2 in alveolar macrophages were exposed to 14 Gy whole-thoracic radiation. At 24 weeks after irradiation, lungs were collected for histological, protein, and mRNA evaluation of pulmonary fibrosis, profibrotic gene expression, and α-smooth muscle actin (α-SMA) expression. Mouse lung fibroblasts were activated with transforming growth factor (TGF)-β1 in the presence or absence of syndecan-2. Cell proliferation, migration, and gel contraction were assessed at different time points. Irradiation resulted in significantly increased mortality and pulmonary fibrosis in wild-type mice that was associated with elevated lung expression of TGF-β1 downstream target genes and cell death compared with irradiated syndecan-2 transgenic mice. In mouse lung fibroblasts, syndecan-2 inhibited α-SMA expression, cell contraction, proliferation, and migration induced by TGF-β1. Syndecan-2 attenuated phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and serum response factor binding to the α-SMA promoter. Syndecan-2 attenuates pulmonary fibrosis in mice exposed to radiation and inhibits TGF-β1-induced fibroblast-myofibroblast differentiation, migration, and proliferation by down-regulating phosphoinositide 3-kinase/serine/threonine kinase/Rho-associated coiled-coil kinase signaling and blocking serum response factor binding to the α-SMA promoter via CD148. These findings suggest that syndecan-2 has potential as an antifibrotic therapy in radiation-induced lung fibrosis.
放射性肺纤维化是接受胸部放疗患者的一种严重并发症。我们之前已经表明，Syndecan-2通过发挥肺泡上皮细胞保护作用来减轻纤维化。在此，我们研究Syndecan-2是否通过抑制成纤维细胞活化来减轻放射性肺纤维化。将C57BL/6野生型小鼠和在肺泡巨噬细胞中过表达人Syndecan-2的转基因小鼠暴露于14 Gy全胸照射。照射后24周，收集肺组织进行肺纤维化、促纤维化基因表达和α-平滑肌肌动蛋白（α-SMA）表达的组织学、蛋白质和mRNA评估。在有或没有Syndecan-2的情况下，用转化生长因子（TGF）-β1激活小鼠肺成纤维细胞。在不同时间点评估细胞增殖、迁移和凝胶收缩。与照射的Syndecan-2转基因小鼠相比，照射导致野生型小鼠死亡率显著增加和肺纤维化，这与TGF-β1下游靶基因的肺表达升高和细胞死亡有关。在小鼠肺成纤维细胞中，Syndecan-2抑制TGF-β1诱导的α-SMA表达、细胞收缩、增殖和迁移。Syndecan-2减弱了磷酸肌醇3激酶/丝氨酸/苏氨酸激酶/Rho相关卷曲螺旋激酶信号传导以及血清反应因子与α-SMA启动子的结合。Syndecan-2减轻暴露于辐射的小鼠的肺纤维化，并通过下调磷酸肌醇3激酶/丝氨酸/苏氨酸激酶/Rho相关卷曲螺旋激酶信号传导并通过CD148阻断血清反应因子与α-SMA启动子的结合来抑制TGF-β1诱导的成纤维细胞向肌成纤维细胞的分化、迁移和增殖。这些发现表明，Syndecan-2在放射性肺纤维化中具有作为抗纤维化治疗的潜力。
