Evaluation of the antifibrotic potency by knocking down SPARC, CCR2 and SMAD3.
Evaluation of the antifibrotic potency by knocking down SPARC, CCR2 and SMAD3.
复制标题
通过敲低 SPARC、CCR2 和 SMAD3 评估抗纤维化效力
DOI：
10.1016/j.ebiom.2018.11.016
复制
发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Ding W;Pu W;Jiang S;Ma Y;Liu Q;Wu W;Chu H;Zou H;Jin L;Wang J;Zhou X
SPARC、CCR2 和 SMAD3 基因参与协调导致硬皮病和其他纤维化疾病纤维化的炎症反应。这些研究的目的是评估这些基因的 siRNA 的协同抗纤维化效力。在博莱霉素诱导的小鼠纤维化中评估了 siRNA 组合的功效。采用苏木精、伊红和马森三色染色评估小鼠皮肤和肺部的病理变化。通过实时 RT-PCR、RNA 测序、蛋白质印迹和 ELISA 评估组织中炎症和纤维化相关基因和蛋白质的表达。通过 Sircol 比色测定法测量非交联原纤维胶原。联合siRNA在博来霉素诱导的小鼠中的应用取得了良好的抗炎和抗纤维化作用。成纤维细胞的活化被抑制，同时炎症受到抑制，这通过治疗减少了 BALF 和/或组织中的炎症细胞和促炎细胞因子来证明。治疗后，成纤维细胞、单核细胞/巨噬细胞、内皮细胞和上皮细胞中正常表达的基因的异常表达得到显着抑制。此外，转录组谱表明，博来霉素诱导的多种生物途径的一些改变通过治疗得到了不同程度的恢复。 SPARC、CCR2 和 SMAD3 基因的组合 siRNA 的应用改善了博来霉素诱导的小鼠的炎症和纤维化。它可能通过控制不同的细胞类型（包括成纤维细胞、单核细胞/巨噬细胞、内皮细胞等）系统地恢复多种生物途径。本文检查的多靶点组合治疗方法可能代表一种新颖且有效的纤维化疗法。概要 针对 Sparc、Ccr2 和 Smad3 的 siRNA 三重组合取得了良好的抗炎和抗纤维化作用。 BALF 和/或组织中炎症细胞和促炎细胞因子的减少证明了炎症的抑制。小鼠组织中成纤维细胞的活化受到抑制，其中 α-Sma 和胶原蛋白显着减少。治疗后，成纤维细胞、单核细胞/巨噬细胞、内皮细胞和上皮细胞中基因的异常表达被重新安装。转录组谱表明，博来霉素诱导的多种生物途径的一些改变通过治疗得到了不同程度的恢复。通过针对Sparc、Ccr2和Smad3三重基因的联合siRNA来控制包括成纤维细胞、单核细胞/巨噬细胞在内的不同细胞类型，内皮细胞系统地恢复了纤维形成的多种信号传导生物途径，这表明了一种新的有效的抗纤维化策略。
The genes of SPARC, CCR2, and SMAD3 are implicated in orchestrating inflammatory response that leads to fibrosis in scleroderma and other fibrotic disorders. The aim of the studies is to evaluate synergistic anti-fibrotic potency of the siRNAs of these genes. The efficacy of the siRNA-combination was evaluated in bleomycin-induced mouse fibrosis. The pathological changes of skin and lungs of the mice were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression of inflammation and fibrosis associated genes and proteins in the tissues were assessed by real-time RT-PCR, RNA sequencing, Western blots and ELISA. Non-crosslinked fibrillar collagen was measured by the Sircol colorimetric assay. The applications of the combined siRNAs in bleomycin-induced mice achieved favorable anti-inflammatory and anti-fibrotic effects. Activation of fibroblasts was suppressed in parallel with inhibition of inflammation evidenced by reduced inflammatory cells and proinflammatory cytokines in the BALF and/or the tissues by the treatment. Aberrant expression of the genes normally expressed in fibroblasts, monocytes/ macrophage, endothelial and epithelial cells were significantly restrained after the treatment. In addition, transcriptome profiles indicated that some bleomycin-induced alterations of multiple biological pathways were recovered to varying degrees by the treatment. The application of the combined siRNAs of SPARC, CCR2, and SMAD3 genes ameliorated inflammation and fibrosis in bleomycin-induced mice. It systemically reinstated multiple biopathways, probably through controlling on different cell types including fibroblasts, monocytes/macrophages, endothelial cells and others. The multi-target-combined therapeutic approach examined herein may represent a novel and effective therapy for fibrosis. Synopsis Triple combination of siRNAs targeting on Sparc, Ccr2 and Smad3 achieved favorable anti-inflammatory and anti-fibrotic effects. Inhibition of inflammation was evidenced by reduced inflammatory cells and proinflammatory cytokines in the BALF and/or the tissues. Activation of fibroblasts was suppressed in mouse tissues in which α-Sma and collagens were significantly reduced. Aberrant expression of the genes in fibroblasts, monocytes/macrophage, endothelial and epithelial cells were reinstalled after the treatment. Transcriptome profiles indicated that some bleomycin-induced alterations of multiple biological pathways were recovered to varying degrees by the treatment. Through combined siRNAs targeting triple genes of Sparc, Ccr2, and Smad3 to control on different cell types including fibroblasts, monocytes/macrophages, endothelial cells systemically recovered multiple signaling biopathways of fibrogenesis, indicating a novel effective strategy for anti-fibrosis.
登录
查看更多内容
影响因子：
37.8
作者：
Kong P;Shinde AV;Su Y;Russo I;Chen B;Saxena A;Conway SJ;Graff JM;Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
16.6
作者：
Lopez-Sanchez, Inmaculada;Lopez-Sanchez, Inmaculada;Dunkel, Ying;Roh, Yoon-Seok;Mittal, Yash;De Minicis, Samuele;Muranyi, Andrea;Singh, Shalini;Shanmugam, Kandavel;Aroonsakool, Nakon;Murray, Fiona;Ho, Samuel B.;Seki, Ekihiro;Brenner, David A.;Ghosh, Pradipta
通讯作者：
Ghosh, Pradipta
影响因子：
3.9
作者：
Piera-Velazquez S;Mendoza FA;Jimenez SA
通讯作者：
Jimenez SA
影响因子：
4.8
作者：
Rehli, M;Niller, HH;Krause, SW
通讯作者：
Krause, SW
影响因子：
27.4
作者：
Raghu H;Lepus CM;Wang Q;Wong HH;Lingampalli N;Oliviero F;Punzi L;Giori NJ;Goodman SB;Chu CR;Sokolove JB;Robinson WH
通讯作者：
Robinson WH