增生性瘢痕的预防与治疗进展

瘢痕是人体创伤修复过程的自然产物,但过度修复将导致病理性瘢痕的形成。增生性瘢痕是常见的病理性瘢痕,引起瘙痒、疼痛、烧灼感和不适,严重影响患者生活。目前可从手术设计、术后应用硅胶膜及注射肉毒素方面预防瘢痕发生,新的治疗方法如局部注射药物、激光治疗及中药治疗等都展现了很好的疗效,有望成为治疗瘢痕的主要选择。本文将结合国内外最新文献对增生性瘢痕防治的进展作一综述。     

多磺酸黏多糖乳膏对兔耳增生性瘢痕的抑制作用及机制研究

【摘要】 目的 探究多磺酸黏多糖乳膏对增生性瘢痕形成的抑制作用及机制。方法 在新西兰白兔（16只）双耳建立直径6 mm的圆形全层创面,构建兔耳增生性瘢痕模型,每只兔耳3个瘢痕创面,左耳瘢痕作为多磺酸黏多糖乳膏实验组,右耳瘢痕为基质对照组,分别外涂多磺酸黏多糖乳膏和基质乳膏,1只兔耳用药量约0.4 g,2次/d,连续6周。分别在用药开始第0天（手术14 d）、14天（手术后28 d）和42天（手术后56 d）取瘢痕组织进行HE染色、Masson染色和免疫组化实验,评估组织病理评分,检测瘢痕厚度、胶原纤维密度和Ⅰ、Ⅲ型胶原蛋白表达及Ⅰ/Ⅲ型胶原蛋白比值。采用t检验和单因素方差分析比较两组各指标差异。结果 HE染色结果显示,与给药前相比,给药42 d对照组存在大量细胞外基质沉积、炎症细胞浸润和局部充血等,而实验组未见明显改变 。给药0、14、42 d,对照组兔耳瘢痕组织病理结构评分明显升高,分别为4.16 ± 1.61、6.50 ± 1.46、6.53 ± 1.34（F = 13.69,P = 0.001）,而实验组无明显变化（4.65 ± 1.52、5.13 ± 1.83、5.38 ± 1.60;F = 0.78,P > 0.05）。Masson染色结果显示,给药42 d对照组胶原纤维含量极高,被染成深蓝色,而实验组胶原纤维含量有所下降 ;随着给药时间的增加,与给药前相比,对照组瘢痕组织厚度明显增加（F = 5.64,P = 0.007）,而实验组无明显变化（F = 1.48,P > 0.05）。免疫组化结果显示,与给药0 d相比,实验组和对照组各时点Ⅲ型胶原蛋白表达均无明显改变（F = 0.22、0.92,均P > 0.05）,但对照组Ⅰ型胶原蛋白表达和Ⅰ/Ⅲ型胶原蛋白比例明显上升（F = 7.47,P < 0.001;F = 4.70,P = 0.005）;给药42 d,与对照组相比,实验组Ⅰ型胶原蛋白表达和Ⅰ/Ⅲ型胶原蛋白比值明显下降（t = 3.04,P = 0.007;t = 2.35,P = 0.030） 。结论 多磺酸黏多糖乳膏局部应用可有效降低瘢痕厚度和抑制胶原纤维增生以及Ⅰ型胶原蛋白表达,预防和抑制瘢痕增生。     

Histopathological differential diagnosis of keloid and hypertrophic scar

Distinguishing hypertrophic scar (HS) from keloid histopathologically is sometimes difficult because thickened hyalinized collagen (keloidal collagen), the hallmark of keloid, is not always detectable and alpha-smooth muscle actin (alpha-SMA), a differentiating marker of HS, is variably expressed in both forms of scar. The aim of this study was to investigate additional distinguishing features to facilitate differentiation between keloid and HS. We compared various histologic features and the expression of alpha-SMA in 40 specimens of keloid and 10 specimens of HS. The features more commonly seen in keloids were: (a) no flattening of the overlying epidermis, (b) no scarring of the papillary dermis, (c) presence of keloidal collagen, (d) absence of prominent vertically oriented blood vessels, (e) presence of prominent disarray of fibrous fascicles/nodules, (f) presence of a tongue-like advancing edge underneath normal-appearing epidermis and papillary dermis, (g) horizontal cellular fibrous band in the upper reticular dermis, and (h) prominent fascia-like fibrous band. The last three features were found in keloid specimens only, including the ones lacking detectable keloidal collagen. Our study confirmed the diagnostic value of keloidal collagen, but it was only found in 55% of keloid specimens. Alpha-SMA expression was found in both HS (70%) and keloid (45%), thus it would not be a differentiating marker. In scars with no detectable keloidal collagen, the presence of the following feature(s) favors the diagnosis of keloid: non-flattened epidermis, non-fibrotic papillary dermis, a tongue-like advancing edge, horizontal cellular fibrous band in the upper reticular dermis, and prominent fascia-like band.     

Prostaglandin E2 inhibits collagen synthesis in dermal fibroblasts and prevents hypertrophic scar formation in vivo

Hypertrophic scarring is a common dermal fibroproliferative disorder characterized by excessive collagen deposition. Prostaglandin E₂ (PGE₂), an important inflammatory product synthesized via the arachidonic acid cascade, has been shown to act as a fibroblast modulator and to possess antifibroblastic activity. However, the mechanism underlying the antifibrotic effect of PGE₂ remains unclear. In this study, we explored the effects of PGE₂ on TGF‐β1‐treated dermal fibroblasts in terms of collagen production and to determine the regulatory pathways involved, as well as understand the antiscarring function of PGE₂ in vivo. We found that PGE₂ inhibited TGF‐β1‐induced collagen synthesis by regulating the balance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP). It did so by upregulating cAMP through the E prostanoid (EP)2 receptor. We determined that inhibition of the TGF‐β1/Smad pathway by PGE₂ is associated with its ability to inhibit collagen synthesis. An in vivo study further confirmed that PGE₂ inhibits hypertrophic scar formation by decreasing collagen production. Our results demonstrate that the novel anti‐scarring function of PGE₂ is achieved by balancing MMPs/TIMP expression and decreasing collagen production.     

Prognostic tools for hypertrophic scar formation based on fundamental differences in systemic immunity

Unpredictable hypertrophic scarring (HS) occurs after approximately 35% of all surgical procedures and causes significant physical and psychological complaints. Parallel to the need to understanding the mechanisms underlying HS formation, a prognostic tool is needed. The objective was to determine whether (systemic) immunological differences exist between patients who develop HS and those who develop normotrophic scars (NS) and to assess whether those differences can be used to identify patients prone to developing HS. A prospective cohort study with NS and HS groups in which (a) cytokine release by peripheral blood mononuclear cells (PBMC) and (b) the irritation threshold (IT) after an irritant (sodium lauryl sulphate) patch test was evaluated. Univariate regression analysis of PBMC cytokine secretion showed that low MCP‐1, IL‐8, IL‐18 and IL‐23 levels have a strong correlation with HS (P < .010‐0.004; AUC = 0.790‐0.883). Notably, combinations of two or three cytokines (TNF‐a, MCP‐1 and IL‐23; AUC: 0.942, Nagelkerke R²: 0.727) showed an improved AUC indicating a better correlation with HS than single cytokine analysis. These combination models produce good prognostic results over a broad probability range (sensitivity: 93.8%, specificity 86.7%, accuracy 90,25% between probability 0.3 and 0.7). Furthermore, the HS group had a lower IT than the NS group and an accuracy of 68%. In conclusion, very fundamental immunological differences exist between individuals who develop HS and those who do not, whereas the cytokine assay forms the basis of a predictive prognostic test for HS formation, the less invasive, easily performed irritant skin patch test is more accessible for daily practice.     

Effect of hematoporphyrin monomethyl ether-mediated photodynamic therapy on hypertrophic scar fibroblasts

Background: Clinical studies have demonstrated that photodynamic therapy (PDT) for hyperplastic dermatosis results in a beneficial outcome. Hypertrophic scar (HS) is a pathological process characterized by fibroblastic hyperproliferation. However, it is unclear whether photochemical interactions between PDT and fibroblasts contribute to a beneficial outcome. To investigate the primary photochemical effects of PDT, we studied the efficacy of 630 nm PDT on human fibroblasts from HS using hematoporphyrin monomethyl ether (HMME) as a photosensitizer. Methods: Fibroblasts were cultured from nontreated HSs, and cells at passage 4–6 were used for the experiments. Morphological and biochemical changes in fibroblasts were assessed by Hoechst 33258 staining and annexin V‐FITC/PI flow cytometry (FCM). Caspase‐3 activity assay and immunofluorescence staining were performed to investigate caspase‐3 expression in fibroblasts. Results: The morphological features of cell apoptosis were viewed under a fluorescent microscope by Hoechst 33258 staining. FCM indicated that the apoptotic rate was significantly increased after HMME–PDT, and caspase‐3 activity was observed. Conclusions: Low‐level exposure to 630 nm PDT mediated by HMME appears to induce fibroblast apoptosis and stimulate caspase‐3 activation. However, the effect of HMME–PDT on fibroblasts needs further investigation to determine its therapeutic potential for HS.     

增生性瘢痕发生和演变过程中成纤维细胞生物学功能变化及其意义

目的 探索增生性瘢痕在发生和演变过程中,成纤维细胞生物学功能变化的规律及其意义.方法 选取人不同时期增生性瘢痕组织和正常皮肤组织,进行HE染色观察.另外,分离和培养不同时期瘢痕和正常皮肤中成纤维细胞,RT-PCR分别检测成纤维细胞在转移生长因子（TGF-β1）、血管内皮细胞生长因子（VEGF）、和Ⅰ、Ⅲ胶原mRNA表达水平的变化.结果 HE染色可见正常皮肤细胞和微血管数目较少,早期瘢痕增多,炎症细胞浸润明显.增生期瘢痕成纤维细胞和微血管增多.随病情进展,微血管呈缩窄倾向.消退期瘢痕成纤维细胞减少,微血管狭窄或闭塞.成熟期瘢痕见微血管、成纤维细胞数目进一步减少,微血管管腔小,大部分开放.RT-PCR检测结果发现,正常皮肤来源的成纤维细胞TGF-β1、VEGF和Ⅰ、Ⅲ胶原mRNA有较低表达,早期瘢痕成纤维细胞TGF-β1、VEGF和Ⅰ、Ⅲ胶原mRNA表达水平开始升高,在增生期表达到达高峰,消退期瘢痕的表达开始下降,到成熟期表达最低.结论 增生性瘢痕发生和演变过程中,成纤维细胞功能存在动态改变,这种动态改变与瘢痕的发生和消退成熟的病理变化相关.     

Growth kinetics of fibroblasts derived from normal skin and hypertrophic scar

In vitro growth kinetics of fibroblasts derived from normal skin and hypertrophic scar were performed using continuous 3H-thymidine labeling method. In fibroblasts derived from normal skin, aging of the donor affects cell growth mainly by growth fraction (GF), but not labeling index (LI) and DNA synthetic time (Ts). When hypertrophic scar-derived fibroblasts are compared with normal fibroblasts, they showed a shorter Ts and lower LI and GF. This result suggests that in hypertrophic scar a small number of fibroblasts proliferate more actively, but most fibroblasts are non-growing cells.     

Mechanical analysis of hypertrophic scar tissue: structural basis for apparent increased rigidity

The mechanical behavior of normal human skin and hypertrophic scar tissue (HST) is compared using constant-strain-rate and successive stress-relaxation uniaxial loading programs in vitro. HST is less extensible, requires more energy to be stretched in the physiologic range, and stores strain energy less efficiently than normal skin. The explanations for the differences observed between the mechanical behavior of normal skin and HST are based on the differences in their composition and structure. We suggest that the collagen fiber network is partially "prealigned" in a crimped tendon-like organization in HST, which reduces its extensibility and raises the strain energy required to stretch it. It is further hypothesized that an incomplete elastic fiber network, an abnormal glycosaminoglycan content, and/or abnormal collagen fiber slippage are responsible for the reduced capacity to return strain energy in the hypertrophic scar tissue. The results of these studies indicate that although HST has been described as stiffer than normal skin, the maximum stiffness of skin and HST are similar. The "apparent" increased rigidity of HST is a result of reduced extensibility rather than a change in its stiffness. This inexensibility may manifest itself by limiting joint mobility in the patient with HST.     

Tacrolimus action pathways in an ointment base for hypertrophic scar prevention in a rabbit ear model

BackgroundTacrolimus is used to prevent unaesthetic scars due to its action on fibroblast activity and collagen production modulation.ObjectivesTo evaluate the action pathways, from the histopathological point of view and in cytokine control, of tacrolimus ointment in the prevention of hypertrophic scars.MethodsTwenty-two rabbits were submitted to the excision of two 1-cm fragments in each ear, including the perichondrium. The right ear received 0.1% and 0.03% tacrolimus in ointment base twice a day in the upper wound and in the lower wound respectively. The left ear, used as the control, was treated with petrolatum. After 30 days, collagen fibers were evaluated using special staining, and immunohistochemistry analyses for smooth muscle actin, TGF-β and VEGF were performed.ResultsThe wounds treated with 0.1% tacrolimus showed weak labeling and a lower percentage of labeling for smooth muscle actin, a higher proportion of mucin absence, weak staining, fine and organized fibers for Gomori's Trichrome, strong staining and organized fibers for Verhoeff when compared to controls. The wounds treated with 0.03% tacrolimus showed weak labeling for smooth muscle actin, a higher proportion of mucin absence, strong staining for Verhoeff when compared to the controls. There was absence of TGF-β and low VEGF expression.Study limitationsThe analysis was performed by a single pathologist. Second-harmonic imaging microscopy was performed in 2 sample areas of the scar.ConclusionsBoth drug concentrations were effective in suppressing TGF-β and smooth muscle actin, reducing mucin, improving the quality of collagen fibers, and the density of elastic fibers, but only the higher concentration influenced elastic fiber organization.     

剪切波弹性成像定量鉴别瘢痕疙瘩与肥厚性瘢痕的初步探讨

目的：探讨剪切波弹性成像技术定量鉴别瘢痕疙瘩与肥厚性瘢痕的价值。方法：选取我院皮肤科临床诊断为瘢痕疙瘩及肥厚性瘢痕患者各30例,比较两组病例的性别、年龄、病灶长轴切面的剪切波弹性成像杨氏模量值。结果：瘢痕疙瘩、肥厚性瘢痕的长轴平均杨氏模量分别为(94.93±25.39) kPa、(24.5±3.62)kPa,差异有统计学意义(P＜0.001)。结论：剪切波弹性成像可定量评价两组病变的组织硬度,为瘢痕疙瘩和肥厚性瘢痕的临床鉴别提供帮助。