Durham, N.C. From the Division of Plastic and Reconstructive Surgery, Department of Surgery, and the Department of Pathology, Duke University Medical Center.
Plast Reconstr Surg. 2011 Nov;128(5):438e-450e. doi: 10.1097/PRS.0b013e31822b7352.
Dermal scarring and scar contracture result in restriction of movement. There are no effective drugs to prevent scarring. RhoA and Rho-associated kinase have emerged as regulators of fibrosis and contracture. Fasudil, a Rho-associated kinase inhibitor, has been demonstrated to have antifibrotic effects in models of liver, renal, and cardiac fibrosis. The role of fasudil in preventing dermal scarring and contractures has not been studied. The authors used a rat model of dermal wound healing to assess the effects of fasudil with regard to the prevention of scarring.
Human scar tissue and surrounding normal skin were immunostained for RhoA and Rho-associated kinase. Full-thickness wounds were created on Wistar-Han rats, and fasudil (30 mg/kg/day) or saline was continuously delivered subcutaneously. Wound contraction was measured by gravitational planimetry. After 21 days, tissue was harvested for Masson's trichrome, hematoxylin and eosin, Ki-67, and CD31 staining. Fibroblast-populated collagen lattices were used 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 Rho-associated kinase in scar tissue compared with surrounding normal tissue. Fasudil inhibited wound contraction as compared with controls. Hematoxylin and eosin and Masson's trichrome 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 the RhoA/Rho-associated kinase pathway plays an important role in wound healing and scar contracture. The authors present data showing that inhibition of Rho-associated kinase hinders fibroblast contractility and may be beneficial in preventing scar contracture.
皮肤瘢痕和瘢痕挛缩导致运动受限。目前尚无有效的药物预防瘢痕形成。RhoA 和 Rho 相关激酶已成为纤维化和挛缩的调节因子。Rho 相关激酶抑制剂法舒地尔已被证明在肝、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得到研究。作者使用皮肤创伤愈合大鼠模型评估了法舒地尔在预防瘢痕形成方面的作用。
对人瘢痕组织和周围正常皮肤进行 RhoA 和 Rho 相关激酶免疫染色。在 Wistar-Han 大鼠上造成全层皮肤创伤，每天皮下持续给予法舒地尔（30mg/kg）或生理盐水。通过重力平板测定法测量伤口收缩。21 天后，采集组织进行 Masson 三色、苏木精和伊红、Ki-67 和 CD31 染色。使用纤维母细胞填充的胶原格子评估法舒地尔对收缩性的机制作用。在法舒地尔存在的情况下评估肌成纤维细胞的形成。
修复重塑阶段的人瘢痕组织中，与周围正常组织相比，瘢痕组织中 RhoA 和 Rho 相关激酶表达增加。与对照组相比，法舒地尔抑制了伤口收缩。各组苏木精和伊红、Masson 三色染色结果相似。法舒地尔并未改变血管生成或增殖。法舒地尔抑制了体外纤维母细胞的收缩性和肌成纤维细胞的形成。
越来越多的证据表明，RhoA/Rho 相关激酶通路在伤口愈合和瘢痕挛缩中起着重要作用。作者提供的数据表明，抑制 Rho 相关激酶会阻碍纤维母细胞的收缩性，可能有益于预防瘢痕挛缩。
