Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease.
Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease.
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DOI：
10.1016/j.jcmgh.2017.12.005
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发表时间：
2018-03
影响因子：
7.2
通讯作者：
Inoue R
中科院分区：
文献类型：
--
作者：
Kurahara LH;Hiraishi K;Hu Y;Koga K;Onitsuka M;Doi M;Aoyagi K;Takedatsu H;Kojima D;Fujihara Y;Jian Y;Inoue R
瞬时受体电位锚蛋白1 （TRPA1）通道在肠固有层中高表达，但其在肠道生理/病理生理中的作用尚不清楚。在这里，我们评估了肌成纤维细胞TRPA1通道在肠道重塑中的功能。用转化生长因子-β1刺激肠肌成纤维细胞系（InMyoFibs）诱导体外纤维化。Trpa1敲除小鼠使用聚集规则间隔短回文重复(CRISPR)/CRISPR相关9 （Cas9）系统生成。采用三硝基苯磺酸（TNBS）周灌胃建立小鼠慢性结肠炎模型。采用克罗恩病（CD）患者肠道标本进行病理染色和定量分析。在InMyoFibs中，TRPA1在TRP家族成员中表达最高。在TNBS慢性结肠炎模型小鼠中，TRPA1-/-敲除小鼠的炎症和纤维化改变程度比野生型小鼠更为突出。强的松龙灌肠一周可抑制野生型小鼠的纤维化病变，但对TRPA1敲除小鼠无抑制作用。类固醇和吡非尼酮诱导Ca2+内流InMyoFibs，这是由选择性TRPA1通道阻滞剂HC-030031拮抗。类固醇和吡非尼酮抵消了转化生长因子-β1诱导的热休克蛋白47、1型胶原和α-平滑肌肌动蛋白的表达，并降低了InMyoFibs中Smad-2磷酸化和心肌素的表达。在CD患者狭窄肠区，TRPA1表达明显升高。TRPA1/热休克蛋白47双阳性细胞在CD患者和tnbs治疗小鼠的狭窄肠区积累。TRPA1除具有抗炎作用外，还可预防肠道纤维化，因此成为高度不可治愈的炎症/纤维化疾病的新治疗靶点。
The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling. An intestinal myofibroblast cell line (InMyoFibs) was stimulated by transforming growth factor-β1 to induce in vitro fibrosis. Trpa1 knockout mice were generated using the Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. A murine chronic colitis model was established by weekly intrarectal trinitrobenzene sulfonic acid (TNBS) administration. Samples from the intestines of Crohn’s disease (CD) patients were used for pathologic staining and quantitative analyses. In InMyoFibs, TRPA1 showed the highest expression among TRP family members. In TNBS chronic colitis model mice, the extents of inflammation and fibrotic changes were more prominent in TRPA1-/- knockout than in wild-type mice. One-week enema administration of prednisolone suppressed fibrotic lesions in wild-type mice, but not in TRPA1 knockout mice. Steroids and pirfenidone induced Ca2+ influx in InMyoFibs, which was antagonized by the selective TRPA1 channel blocker HC-030031. Steroids and pirfenidone counteracted transforming growth factor-β1–induced expression of heat shock protein 47, type 1 collagen, and α-smooth muscle actin, and reduced Smad-2 phosphorylation and myocardin expression in InMyoFibs. In stenotic intestinal regions of CD patients, TRPA1 expression was increased significantly. TRPA1/heat shock protein 47 double-positive cells accumulated in the stenotic intestinal regions of both CD patients and TNBS-treated mice. TRPA1, in addition to its anti-inflammatory actions, may protect against intestinal fibrosis, thus being a novel therapeutic target for highly incurable inflammatory/fibrotic disorders.
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影响因子：
4.9
作者：
Coward, Stephanie;Kuenzig, M. Ellen;Kaplan, Gilaad G.
通讯作者：
Kaplan, Gilaad G.
DOI：
10.3410/b2-78
发表时间：
2010-11-11
期刊：
F1000 biology reports
影响因子：
--
作者：
Hinz B;Gabbiani G
通讯作者：
Gabbiani G
影响因子：
20.1
作者：
Du J;Xie J;Zhang Z;Tsujikawa H;Fusco D;Silverman D;Liang B;Yue L
通讯作者：
Yue L
影响因子：
24.5
作者：
Bertin S;Aoki-Nonaka Y;Lee J;de Jong PR;Kim P;Han T;Yu T;To K;Takahashi N;Boland BS;Chang JT;Ho SB;Herdman S;Corr M;Franco A;Sharma S;Dong H;Akopian AN;Raz E
通讯作者：
Raz E
DOI：
10.1016/j.ijom.2015.06.015
发表时间：
2015-12-01
影响因子：
2.4
作者：
Jiang, X.;Zhang, Y.;Sun, G.
通讯作者：
Sun, G.