Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds.
Complex fibroblast response to glucocorticoids may underlie variability of clinical efficacy in the vocal folds.
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DOI：
10.1038/s41598-020-77445-9
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发表时间：
2020-11-24
影响因子：
4.6
通讯作者：
Branski RC
中科院分区：
文献类型：
--
作者：
Nakamura R;Mukudai S;Bing R;Garabedian MJ;Branski RC
与增生性疤痕和疤痕疙瘩类似，糖皮质激素（GC）治疗声带损伤的疗效差异很大。我们先前报道地塞米松增强转化生长因子（TGF）-β的促纤维化作用是临床结局不一致的潜在机制。在本研究中，我们试图确定GC影响纤维化反应的机制以及这些作用的潜在机制，重点是TGF-β和核受体亚家族4 A组成员1（NR 4A 1）信号传导。用三种常用的GC + /-TGF-β1处理人VF成纤维细胞（HVOX）。糖皮质激素受体（GR：NR 3C 1）的磷酸化和NR 4A 1的活化通过蛋白质印迹分析。通过qPCR分析参与纤维化反应的基因，包括ACTA 2、TGFBR 1和TGFBR 2。进行RNA-seq以鉴定地塞米松诱导的基因表达的总体变化。GC增强GR在Ser 211的磷酸化和TGF-β诱导的ACTA 2表达。地塞米松在TGF-β1存在的情况下上调TGFBR 1和TGFBR 2，并增加活性NR 4A 1。RNA-seq结果证实了地塞米松影响的多种途径，包括TGF-β信号传导。在GC中观察到TGF-β的协同促纤维化作用，并且似乎至少部分地通过TGF-β受体的上调介导。地塞米松表现出多种基因表达调控，包括与GC的抗纤维化潜力一致的NR 4A 1上调。
Similar to the hypertrophic scar and keloids, the efficacy of glucorticoids (GC) for vocal fold injury is highly variable. We previously reported dexamethasone enhanced the pro-fibrotic effects of transforming growth factor (TGF)-β as a potential mechanism for inconsistent clinical outcomes. In the current study, we sought to determine the mechanism(s) whereby GCs influence the fibrotic response and mechanisms underlying these effects with an emphasis on TGF-β and nuclear receptor subfamily 4 group A member 1 (NR4A1) signaling. Human VF fibroblasts (HVOX) were treated with three commonly-employed GCs+ /-TGF-β1. Phosphorylation of the glucocorticoid receptor (GR:NR3C1) and activation of NR4A1 was analyzed by western blotting. Genes involved in the fibrotic response, including ACTA2, TGFBR1, and TGFBR2 were analyzed by qPCR. RNA-seq was performed to identify global changes in gene expression induced by dexamethasone. GCs enhanced phosphorylation of GR at Ser211 and TGF-β-induced ACTA2 expression. Dexamethasone upregulated TGFBR1, and TGFBR2 in the presence of TGF-β1 and increased active NR4A1. RNA-seq results confirmed numerous pathways, including TGF-β signaling, affected by dexamethasone. Synergistic pro-fibrotic effects of TGF-β were observed across GCs and appeared to be mediated, at least partially, via upregulation of TGF-β receptors. Dexamethasone exhibited diverse regulation of gene expression including NR4A1 upregulation consistent with the anti-fibrotic potential of GCs.
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影响因子：
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作者：
Aigner, Achim
通讯作者：
Aigner, Achim
影响因子：
--
作者：
Lee, Sang-Hyuk;Yeo, Jang-Ok;Jin, Sung-Min
通讯作者：
Jin, Sung-Min
NR4A1是声带纤维化的内源性抑制剂。
DOI：
10.1002/lary.26678
发表时间：
2017-09
期刊：
The Laryngoscope
影响因子：
--
作者：
Hiwatashi N;Bing R;Kraja I;Branski RC
通讯作者：
Branski RC
DOI：
10.1097/01.moo.0000162261.49739.b7
发表时间：
2005-06-01
影响因子：
1.6
作者：
Hirano, Shigeru
通讯作者：
Hirano, Shigeru
DOI：
10.1097/00005373-199502000-00030
发表时间：
1995-02-01
影响因子：
--
作者：
BOYADJIEV, C;POPCHRISTOVA, E;MAZGALOVA, J
通讯作者：
MAZGALOVA, J