Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1.
Ciprofloxacin has antifibrotic effects in scleroderma fibroblasts via downregulation of Dnmt1 and upregulation of Fli1.
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DOI：
10.3892/ijmm.2012.1150
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发表时间：
2012-12
影响因子：
5.4
通讯作者：
Trojanowska M
中科院分区：
文献类型：
--
作者：
Bujor AM;Haines P;Padilla C;Christmann RB;Junie M;Sampaio-Barros PD;Lafyatis R;Trojanowska M
系统性硬化症（SSc）的特征在于皮肤和内脏的纤维化。本研究旨在研究环丙沙星（一种与基质重塑有关的氟喹诺酮类抗生素）对SSc患者皮肤和肺成纤维细胞的影响。用环丙沙星处理SSc患者和健康受试者的皮肤和肺成纤维细胞。Western blotting分析蛋白质水平，RT-PCR检测mRNA表达。药理学抑制剂UO 126用于阻断Erk 1/2信号传导。SSc真皮成纤维细胞表现出显着减少胶原蛋白I型mRNA和蛋白质水平抗生素治疗后，而健康的真皮成纤维细胞对环丙沙星不太敏感，下调胶原蛋白仅在蛋白质水平。结缔组织生长因子（CCN 2）的基因表达显着降低，基质金属蛋白酶1（MMP 1）水平提高环丙沙星治疗后，在健康和SSc成纤维细胞在相似的程度。环丙沙星诱导Erk 1/2磷酸化，Erk 1/2阻断剂完全阻止MMP 1上调。然而，Smad 1和Smad 3响应TGFβ的激活不受影响。朋友白血病整合因子1（Fli 1），胶原蛋白的转录抑制因子的表达，增加治疗后与环丙沙星仅在SSc成纤维细胞，这是伴随着DNA甲基转移酶1（Dnmt 1）的水平下降。在Ssc-间质性肺病（ILD）肺成纤维细胞中观察到类似的作用。总之，我们的研究表明，环丙沙星通过下调Dnmt 1，上调Fli 1和诱导MMP 1基因表达，通过Erk 1/2依赖性机制，在SSc皮肤和肺成纤维细胞中具有抗纤维化作用。因此，我们的数据表明，环丙沙星可能是一个有吸引力的治疗SSc皮肤和肺纤维化。
Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. The present study was undertaken to examine the effects of ciprofloxacin, a fluoroquinolone antibiotic implicated in matrix remodeling, on dermal and lung fibroblasts obtained from SSc patients. Dermal and lung fibroblasts from SSc patients and healthy subjects were treated with ciprofloxacin. Western blotting was used to analyze protein levels and RT-PCR was used to measure mRNA expression. The pharmacologic inhibitor UO126 was used to block Erk1/2 signaling. SSc dermal fibroblasts demonstrated a significant decrease in collagen type I mRNA and protein levels after antibiotic treatment, while healthy dermal fibroblasts were less sensitive to ciprofloxacin, downregulating collagen only at the protein levels. Connective tissue growth factor (CCN2) gene expression was significantly reduced and matrix metalloproteinase 1 (MMP1) levels were enhanced after ciprofloxacin treatment to a similar extent in healthy and SSc fibroblasts. Ciprofloxacin induced Erk1/2 phosphorylation, and Erk1/2 blockade completely prevented MMP1 upregulation. However, Smad1 and Smad3 activation in response to TGFβ was not affected. The expression of friend leukemia integration factor 1 (Fli1), a transcriptional repressor of collagen, was increased after treatment with ciprofloxacin only in SSc fibroblasts, and this was accompanied by a decrease in the levels of DNA methyltransferase 1 (Dnmt1). Similar effects were observed in SSc-interstitial lung disease (ILD) lung fibroblasts. In summary, our study demonstrates that ciprofloxacin has antifibrotic actions in SSc dermal and lung fibroblasts via the downregulation of Dnmt1, the upregulation of Fli1 and induction of MMP1 gene expression via an Erk1/2-dependent mechanism. Thus, our data suggest that ciprofloxacin may be an attractive therapy for SSc skin and lung fibrosis.
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影响因子：
4.8
作者：
Nakerakanti, Sashidhar S.;Kapanadze, Bagrat;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
影响因子：
6
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Trojanowska, M
影响因子：
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作者：
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通讯作者：
Varga, J
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Reviglio VE;Hakim MA;Song JK;O'Brien TP
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O'Brien TP