Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts.
Inhibition of Plasminogen Activator Inhibitor-1 Attenuates Transforming Growth Factor-β-Dependent Epithelial Mesenchymal Transition and Differentiation of Fibroblasts to Myofibroblasts.
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DOI：
10.1371/journal.pone.0148969
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Kohno N
中科院分区：
文献类型：
--
作者：
Omori K;Hattori N;Senoo T;Takayama Y;Masuda T;Nakashima T;Iwamoto H;Fujitaka K;Hamada H;Kohno N
转化生长因子-β（Transforming growth factor-β，TGF-β）在肺纤维化的发病机制中起着重要作用，纤溶酶原激活物抑制剂-1（plasminogen activator inhibitor-1，派-1）也在其中发挥着重要作用。还已知TGF-β是派-1的最强诱导剂。为了研究派-1和TGF-β在纤维化过程中的联系，我们评估了派-1特异性抑制剂SK-216在TGF-β依赖性上皮-间质转化（EMT）和成纤维细胞向肌成纤维细胞分化中的作用。在人肺泡上皮A549细胞中，用TGF-β处理诱导EMT，而与SK-216共处理减弱EMT的发生。SK-216对TGF-β诱导的EMT的抑制作用也在使用小鼠上皮LA-4细胞的实验中得到证实。SK-216阻断EMT也能抑制TGF-β诱导的A549细胞内源性派-1和TGF-β的产生。SK-216的这些作用不太可能通过抑制Smad或ERK途径介导。使用人肺成纤维细胞MRC-5细胞，我们证明SK-216抑制成纤维细胞向肌成纤维细胞的TGF-β依赖性分化。我们还在人原代肺成纤维细胞中观察到SK-216的这种抑制作用。根据这些体外结果，我们测试了SK-216对经气管内注射博来霉素的小鼠的口服给药。我们发现SK-216降低了博莱霉素诱导的小鼠肺纤维化的程度。尽管尚未确定TGF-β和派-1之间关于纤维化过程的联系的确切机制，但派-1似乎在TGF-β的促纤维化性质上充当有效的下游效应物。另外，通过派-1抑制剂抑制派-1活性，即使在体内也发挥抗纤维化作用。这些数据表明，靶向派-1作为TGF-β的下游效应物可能是肺纤维化的有希望的治疗策略。
Transforming growth factor-β (TGF-β) is central during the pathogenesis of pulmonary fibrosis, in which the plasminogen activator inhibitor-1 (PAI-1) also has an established role. TGF-β is also known to be the strongest inducer of PAI-1. To investigate the link between PAI-1 and TGF-β in fibrotic processes, we evaluated the effect of SK-216, a PAI-1-specific inhibitor, in TGF-β-dependent epithelial-mesenchymal transition (EMT) and fibroblast to myofibroblast differentiation. In human alveolar epithelial A549 cells, treatment with TGF-β induced EMT, whereas co-treatment with SK-216 attenuated the occurrence of EMT. The inhibition of TGF-β-induced EMT by SK-216 was also confirmed in the experiment using murine epithelial LA-4 cells. Blocking EMT by SK-216 inhibited TGF-β-induced endogenous production of PAI-1 and TGF-β in A549 cells as well. These effects of SK-216 were not likely mediated by suppressing either Smad or ERK pathways. Using human lung fibroblast MRC-5 cells, we demonstrated that SK-216 inhibited TGF-β-dependent differentiation of fibroblasts to myofibroblasts. We also observed this inhibition by SK-216 in human primary lung fibroblasts. Following these in vitro results, we tested oral administration of SK-216 into mice injected intratracheally with bleomycin. We found that SK-216 reduced the degree of bleomycin-induced pulmonary fibrosis in mice. Although the precise mechanisms underlying the link between TGF-β and PAI-1 regarding fibrotic process were not determined, PAI-1 seems to act as a potent downstream effector on the pro-fibrotic property of TGF-β. In addition, inhibition of PAI-1 activity by a PAI-1 inhibitor exerts an antifibrotic effect even in vivo. These data suggest that targeting PAI-1 as a downstream effector of TGF-β could be a promising therapeutic strategy for pulmonary fibrosis.