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Abstract：
Silicone implant-based augmentation rhinoplasty or mammoplasty induces capsular contracture, which has been acknowledged as a process that develops an abnormal fibrotic capsule associated with the immune response to allogeneic materials. However, the signaling pathways leading to the nasal fibrosis remain poorly investigated. We aimed to explore the molecular mechanism underlying the pathogenesis of nasal capsular contracture, with a specific research interest in the signaling pathways involved in fibrotic development at the advanced stage of contracture. By examining our recently obtained RNA sequencing data and global gene expression profiling between grade II and grade IV nasal capsular tissues, we found that both the RAP1 and JAK/STAT signaling pathways were hyperactive in the contracted capsules. This was verified on quantitative real-time PCR which demonstrated upregulation of most of the representative component signatures in these pathways. Loss-of-function assays through siRNA-mediated Rap1 silencing and/or small molecule-directed inhibition of JAK/STAT pathway in ex vivo primary nasal fibroblasts caused a series of dramatic behavioral and functional changes, including decreased cell viability, increased apoptosis, reduced secretion of proinflammatory cytokines, and synthesis of type I collagen, compared to control cells, and indicating the essential role of the RAP1 and JAK/STAT signaling pathways in nasal capsular fibrosis. Our results sheds light on targeting downstream signaling pathways for the prevention and therapy of silicone implant-induced nasal capsular contracture.
摘要：
基于硅胶植入物的隆鼻术或乳房成形术可引起包膜挛缩，这已被认为是一个过程，发展一个异常的纤维化包膜相关的免疫反应的同种异体材料。然而,导致鼻部纤维化的信号通路仍未得到充分研究.我们旨在探讨鼻囊挛缩发病的分子机制，对挛缩晚期纤维化发展中涉及的信号通路有特别的研究兴趣。通过检查我们最近获得的RNA测序数据和II级和IV级鼻囊组织之间的整体基因表达谱，我们发现RAP1和JAK/STAT信号通路在收缩胶囊中都是过度活跃的.这在定量实时PCR上得到证实,其证明了这些途径中大多数代表性组分特征的上调。通过siRNA介导的Rap1沉默和/或小分子定向抑制体外原代鼻成纤维细胞JAK/STAT通路的功能丧失试验，引起了一系列剧烈的行为和功能变化，包括细胞活力下降，细胞凋亡增加，促炎细胞因子分泌减少，I型胶原蛋白的合成，与对照细胞相比，并表明RAP1和JAK/STAT信号通路在鼻包膜纤维化中的重要作用。我们的结果为靶向下游信号通路预防和治疗硅胶植入物引起的鼻囊挛缩提供了启示。
