Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase.
Wound contraction is attenuated by fasudil inhibition of Rho-associated kinase.
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DOI：
10.1097/prs.0b013e31822b7352
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发表时间：
2011-11
影响因子：
3.6
通讯作者：
Levinson H
中科院分区：
文献类型：
--
作者：
Bond JE;Kokosis G;Ren L;Selim MA;Bergeron A;Levinson H
皮肤瘢痕和瘢痕挛缩导致活动受限。没有有效的药物来防止疤痕。RhoA和Rho相关激酶（ROCK）已成为纤维化和挛缩的调节剂。法舒地尔是一种ROCK抑制剂，已被证明在肝、肾和心脏纤维化模型中具有抗纤维化作用。法舒地尔在预防皮肤瘢痕和挛缩中的作用尚未研究。我们使用大鼠皮肤伤口愈合模型来评估法舒地尔预防瘢痕形成的作用。对人瘢痕组织和周围正常皮肤进行RhoA和ROCK免疫染色。在Wistar-han大鼠上制造全层伤口，并连续皮下递送法舒地尔（30 mg/kg/d）或生理盐水。通过重力面积测量法测量伤口收缩。21 d后取组织行Masson三色、H&E、Ki-67和CD-31染色。使用成纤维细胞填充的胶原晶格来评估法舒地尔对收缩性的机械作用。在存在法舒地尔的情况下评估肌成纤维细胞形成。与周围正常组织相比，处于修复的重塑阶段的人类瘢痕组织显示出瘢痕组织中RhoA和ROCK的表达增加。与对照相比，法舒地尔抑制伤口收缩。两组之间的H&E和Masson相似。法舒地尔不改变血管生成或增殖。法舒地尔在体外抑制成纤维细胞收缩性和肌成纤维细胞形成。越来越多的证据表明RhoA/ROCK通路在创伤愈合和瘢痕挛缩中起重要作用。我们目前的数据表明，抑制ROCK会阻碍成纤维细胞的收缩性，可能有利于预防瘢痕挛缩。
Dermal scarring and scar contracture result in restriction of movement. There are no effective drugs to prevent scarring. RhoA and Rho Associated kinase (ROCK) have emerged as regulators of fibrosis and contracture. Fasudil, a ROCK inhibitor, has been demonstrated to have anti-fibrotic effects in models of liver, renal and cardiac fibrosis. The role of fasudil in preventing dermal scarring and contractures has not been studied. We use a rat model of dermal wound healing to assess the effects of fasudil for preventing scarring. Human scar tissue and surrounding normal skin were immunostained for RhoA and ROCK. Full-thickness wounds were created on Wistar-han rats and fasudil (30mg/kg/d) or saline were continuously delivered subcutaneously. Wound contraction was measured by gravitational planimetry. After 21d, tissue was harvested for Masson’s trichrome, H&E, Ki-67 and CD-31 staining. Fibroblast populated collagen lattices were utilized to assess the mechanistic effects of fasudil on contractility. Myofibroblast formation was assessed in the presence of fasudil. Human scar tissue in the remodeling phase of repair showed increased expression of RhoA and ROCK in scar tissue compared to surrounding normal tissue. Fasudil inhibited wound contraction as compared to controls. H&E and Masson’s were similar between groups. Fasudil did not alter angiogenesis or proliferation. Fasudil inhibited fibroblast contractility, and myofibroblast formation in vitro. There is growing evidence that RhoA/ROCK pathway plays an important role in wound healing and scar contracture. We present data that inhibition of ROCK hinders fibroblast contractility and may be beneficial in preventing scar contracture.