Kloeters Oliver, Jia Sheng-Xian, Roy Nakshatra, Schultz Gregory S, Leinfellner Gabrielle, Mustoe Thomas A
Division of Plastic and Reconstructive Surgery, Wound Healing Research Laboratory, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Wound Repair Regen. 2007 May-Jun;15(3):341-9. doi: 10.1111/j.1524-475X.2007.00236.x.
Impaired reepithelialization is a hallmark of chronic, ischemic wounds; however, the pathogenesis of the delayed reepithelialization in these wounds remains poorly understood. Transforming growth factor beta is involved in both the normal and hypoxic wound-healing response and exogenous overexpression of Smad3, which has been known to accelerate reepithelialization. Recently, it was shown in the rabbit ear dermal ulcer model that Ad-Smad3 injection enhanced reepithelialization and granulation tissue formation suggesting a positive effect of Smad3 on wound healing. However, little is known about the role of Smad3 in the ischemic wound healing process. In this study, we examined the effect of Smad3 in an ischemic wound model. Ad-Smad3 or Ad-LacZ (10(8) pfu/wound) was injected into either ear of white New Zealand rabbits. Twenty-four hours later, these ears were rendered ischemic using an established model, and four 7 mm full-thickness punch wounds were made on each ear. Histological evaluation showed a significant increase in reepithelialization parameters in Ad-Smad3-transfected wounds (p<0.01). In contrast, granulation tissue parameters were not affected by Smad3 in ischemia. Smad4 and Smad7 mRNA-expression was not affected by Smad3 overexpression. Connective tissue growth factor protein was up-regulated under ischemic conditions but was unaffected by Smad3 transfection in both ischemic and nonischemic wounds. Our results suggest an enhancing effect of Smad3 on reepithelialization in an ischemic wound model that, in turn, might provide novel therapeutic options. Furthermore, the lack of alteration of Smad-dependent intermediates by Smad3 overexpression suggests the activation of Smad-independent pathways in ischemia.
再上皮化受损是慢性缺血性伤口的一个标志；然而，这些伤口中再上皮化延迟的发病机制仍知之甚少。转化生长因子β参与正常和缺氧伤口愈合反应，并且已知Smad3的外源性过表达可加速再上皮化。最近，在兔耳真皮溃疡模型中发现，注射Ad-Smad3可增强再上皮化和肉芽组织形成，提示Smad3对伤口愈合有积极作用。然而，关于Smad3在缺血性伤口愈合过程中的作用知之甚少。在本研究中，我们检测了Smad3在缺血性伤口模型中的作用。将Ad-Smad3或Ad-LacZ（10⁸ pfu/伤口）注射到白色新西兰兔的一只耳朵中。24小时后，使用已建立的模型使这些耳朵缺血，并在每只耳朵上制作4个7毫米全层打孔伤口。组织学评估显示，Ad-Smad3转染伤口的再上皮化参数显著增加（p<0.01）。相比之下，肉芽组织参数在缺血状态下不受Smad3影响。Smad4和Smad7 mRNA表达不受Smad3过表达的影响。结缔组织生长因子蛋白在缺血条件下上调，但在缺血和非缺血伤口中均不受Smad3转染的影响。我们的结果表明，Smad3对缺血性伤口模型中的再上皮化有增强作用，这反过来可能提供新的治疗选择。此外，Smad3过表达未改变Smad依赖的中间体，提示在缺血中激活了Smad非依赖途径。
