Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor
Treatment of Intestinal Fibrosis in Experimental Inflammatory Bowel Disease by the Pleiotropic Actions of a Local Rho Kinase Inhibitor
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DOI：
10.1053/j.gastro.2017.06.013
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发表时间：
2017-10-01
期刊：
影响因子：
29.4
通讯作者：
Laukens, Debby
中科院分区：
文献类型：
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作者：
Holvoet, Tom;Devriese, Sarah;Laukens, Debby
背景：肠纤维化导致（亚）梗阻是克罗恩病（CD）的常见并发症。Rho激酶（ROCK）在TGF β诱导的肌成纤维细胞活化中发挥多种作用，其可以是治疗靶点。由于全身性ROCK抑制会引起心血管副作用，我们评估了局部作用的ROCK抑制剂（AMA0825）对肠纤维化的影响。方法：使用葡聚糖硫酸钠（DSS）和过继性T细胞转移在小鼠模型中评估纤维化。在不同细胞类型和CD活检培养物中研究了AMA 0825的体外和离体作用。研究结果：ROCK在人肠道的成纤维细胞、上皮细胞、内皮细胞和肌肉细胞中表达，并在发炎和纤维化组织中被激活。在2种纤维化模型中，AMA0825预防性治疗抑制了肌成纤维细胞积聚、促纤维化因子表达和纤维化组织积聚，而不影响临床疾病活动和组织学炎症。ROCK抑制逆转了慢性DSS模型中建立的纤维化，并阻碍了狭窄CD活检组织的离体促纤维化蛋白分泌。AMA0825减少TGF β 1诱导的肌红蛋白相关转录因子（MRTF）和p38丝裂原活化蛋白激酶（MAPK）的活化，下调基质金属蛋白酶、胶原蛋白和成纤维细胞分泌的IL 6。在这些细胞中，ROCK抑制增强了自噬，这是所观察到的胶原蛋白和IL 6产生减少所必需的。AMA0825不影响其他ROCK阳性细胞类型的促炎细胞因子分泌，证实了对纤维化的选择性体内作用。结论：局部ROCK抑制通过减少MRTF和p38 MAPK激活并增加成纤维细胞中的自噬来预防和逆转肠纤维化。总体而言，我们的研究结果表明，局部ROCK抑制作为CD的附加治疗有希望对抗纤维化。
BACKGROUND: Intestinal fibrosis resulting in (sub) obstruction is a common complication of Crohn's disease (CD). Rho kinases (ROCKs) play multiple roles in TGFb-induced myofibroblast activation that could be therapeutic targets. Because systemic ROCK inhibition causes cardiovascular side effects, we evaluated the effects of a locally acting ROCK inhibitor (AMA0825) on intestinal fibrosis. METHODS: Fibrosis was assessed in mouse models using dextran sulfate sodium (DSS) and adoptive T-cell transfer. The in vitro and ex vivo effects of AMA0825 were studied in different cell types and in CD biopsy cultures. RESULTS: ROCK is expressed in fibroblastic, epithelial, endothelial, and muscle cells of the human intestinal tract and is activated in inflamed and fibrotic tissue. Prophylactic treatment with AMA0825 inhibited myofibroblast accumulation, expression of pro-fibrotic factors, and accumulation of fibrotic tissue without affecting clinical disease activity and histologic inflammation in 2 models of fibrosis. ROCK inhibition reversed established fibrosis in a chronic DSS model and impeded ex vivo pro-fibrotic protein secretion from stenotic CD biopsies. AMA0825 reduced TGFb1-induced activation of myocardin-related transcription factor (MRTF) and p38 mitogen-activated protein kinase (MAPK), down-regulating matrix metalloproteinases, collagen, and IL6 secretion from fibroblasts. In these cells, ROCK inhibition potentiated autophagy, which was required for the observed reduction in collagen and IL6 production. AMA0825 did not affect pro-inflammatory cytokine secretion from other ROCK-positive cell types, corroborating the selective in vivo effect on fibrosis. CONCLUSIONS: Local ROCK inhibition prevents and reverses intestinal fibrosis by diminishing MRTF and p38 MAPK activation and increasing autophagy in fibroblasts. Overall, our results show that local ROCK inhibition is promising for counteracting fibrosis as an add-on therapy for CD.