MAP kinase mediates silica-induced fibrotic nodule formation and collagen accumulation in fibroblasts.

Li Y; Kilani RT; Hartwell RGhahary A

摘要

It is well known that silica generates fibrosis around them in animals and human. However, the pathogenesis and mechanism of silica-induced fibrosis are still poorly understood. Here, we established a new strategy through which the effects of silica on fibrotic nodule formation, key extracellular matrix accumulation, and the mechanism involved were explored. To achieve this, human dermal fibroblasts were directly exposed to silica gel for various durations. Fibrotic nodule formation was evaluated by their microscopic appearance, type-1 procollagen, and fibronection expression in cell lysate and MMP-1 and-3 in conditioned media were analyzed by Western blotting. The results show an easily formation of nodule-like structures around silica gel in an in vitro-cultured system. The findings further revealed that silica gel stimulates collagen and fibronectin expression, while down-regulates matrix metalloproteinase-1 and -3 (MMP-1 and MMP-3) released in conditioned medium. To explore the mechanism involved, P38 and ERK1/2 Mitogen-Activated Protein Kinase (MAPK) signaling pathways were evaluated. Result showed that silica inhibits P38 and extracellular signal-regulated kinases (ERK1/2) MAP kinase phosphorylation. The addition of ERK1/2 inhibitor increases silica-stimulated type-1 collagen expression, reduces MMP-1 release and further enhances silica-induced nodule formation in dermal fibroblasts. These findings indicate that the inhibition of ERK1/2 MAPK signaling pathway may contribute to silica-caused fibrosis. In summary, our findings suggest that silica can directly cause fibrotic phenotype when fibroblasts contact with silica particles independent of any inflammation and other factors may exist in an in vivo condition.

机译：众所周知,二氧化硅产生纤维化周围的动物和人类。silica-induced的发病机理和机制纤维化仍知之甚少。建立了一个通过的新战略石英纤维结节形成的影响,关键的细胞外基质堆积,机制进行了探讨。这一点,人类皮肤成纤维细胞直接为各种时间暴露于硅胶。纤维结节的形成是由他们的评价显微镜图像,1型胶原,和fibronection表达细胞溶解产物和金属蛋白酶- 1和3在媒体条件进行了分析西方墨点法。nodule-like结构在硅的形成凝胶在培养的一个系统。进一步表明硅胶刺激胶原蛋白、纤粘连蛋白表达,而下调矩阵metalloproteinase-1和3在条件培养液(金属蛋白酶- 1和MMP-3)释放。探索所涉及的机制,P38和ERK1/2增殖蛋白激酶(MAPK)信号途径进行评估。硅抑制P38和细胞外signal-regulated激酶(ERK1/2) MAP激酶磷酸化。增加silica-stimulated 1型胶原蛋白表达,减少金属蛋白酶- 1释放,进一步提高silica-induced结节形成真皮成纤维细胞。的抑制ERK1/2 MAPK信号通路可能导致silica-caused纤维化。总结,我们的研究表明,二氧化硅直接导致纤维化的表型成纤维细胞与二氧化硅粒子独立于任何炎症和其他因素可能存在于体内的状况。

MAP kinase mediates silica-induced fibrotic nodule formation and collagen accumulation in fibroblasts.

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