Profibrotic role of WNT10A via TGF-β signaling in idiopathic pulmonary fibrosis.
Profibrotic role of WNT10A via TGF-β signaling in idiopathic pulmonary fibrosis.
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DOI：
10.1186/s12931-016-0357-0
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发表时间：
2016-04-12
影响因子：
5.8
通讯作者：
Mukae H
中科院分区：
文献类型：
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作者：
Oda K;Yatera K;Izumi H;Ishimoto H;Yamada S;Nakao H;Hanaka T;Ogoshi T;Noguchi S;Mukae H
WNT/β-catenin信号传导在特发性肺纤维化（IPF）的发病机制中起重要作用;然而，WNT 10A通过转化生长因子（TGF）-β信号传导的作用仍不清楚。我们评估了博来霉素（BLM）处理的小鼠中WNT 10A和TGF-β的表达以及TGF-β或BLM与WNT 10A之间的体外相互作用。此外，我们研究了接受电视辅助胸腔镜手术的IPF患者，以确定WNT 10A表达是否与生存有关。在BLM处理的小鼠中观察到WNT 10A和TGF-β表达增加。实时PCR和荧光素酶报告基因测定证明了TGF-β给药后成纤维细胞中WNT 10A和胶原蛋白的水平增加。相反，WNT 10A siRNA处理抑制了转染的成纤维细胞中胶原蛋白的合成。Kaplan-Meier生存分析表明，与阴性表达的IPF患者相比，WNT 10A阳性表达的IPF患者的生存率有降低的趋势（风险比5.351，95% CI 1.703-16.82; p = 0.0041）。发现WNT 10A的过表达显著预测IPF的急性加重（AE-IPF）（比值比13.69，95%CI 1.728-108.5; p = 0.013）。WNT 10A通过TGF-β活化在IPF的发病机制中起重要作用，它也可能是AE-IPF发作的敏感预测因子。
WNT/β-catenin signaling plays an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF); however, the role of WNT10A via transforming growth factor (TGF)-β signaling remains unclear. We evaluated the expression of WNT10A and TGF-β in bleomycin (BLM)-treated mice and the interactions between TGF-β or BLM and WNT10A in vitro. Additionally, we investigated IPF patients who underwent video-assisted thoracoscopic surgery to determine whether the WNT10A expression is related to the survival. Increased WNT10A and TGF-β expressions were noted in the BLM-treated mice. Real-time PCR and luciferase reporter assays demonstrated the levels of WNT10A and collagen in the fibroblasts cells to increase after TGF-β administration. Conversely, WNT10A siRNA treatment inhibited the synthesis of collagen in the transfected fibroblasts cells. A Kaplan-Meier survival analysis demonstrated a tendency toward a poor survival among the IPF patients with a WNT10A-positive expression compared to those with a negative expression (Hazard ratio 5.351, 95 % CI 1.703-16.82; p = 0.0041). An overexpression of WNT10A was found to be significantly predictive of an acute exacerbation of IPF (AE-IPF) (Odds ratio 13.69, 95 % CI 1.728-108.5; p = 0.013). WNT10A plays an important role in the pathogenesis of IPF via TGF-β activation and it may also be a sensitive predictor for the onset of an AE-IPF.