The effect of the anti-allergic agent avil on abnormal scar fibroblasts.

Abnormal wound healing in humans leads to the formation of hypertrophic scar and keloids. These abnormal scars accumulate excessive extracellular matrix proteins through increased synthesis as well as decreased degradation. In order to find a therapeutic control for scar formation, we investigated the effect of avil (pheniramine maleate) on fibroblasts cultured from abnormal scars in comparison to normal skin. We observed a decrease in the proliferation rate in cells from normal skin (39%), hypertrophic scar (44%), keloid (63%) and in DNA synthesis in cells from normal skin (50%), hypertrophic scar (55%) and keloid (63%) treated with 8 mM avil (72 h). The rate of decrease in collagen synthesis in normal skin (44%), hypertrophic scar (74%) and keloid fibroblast (73%) correlated with changes in DNA synthesis.     

性激素受体在瘢痕中的表达及与细胞周期调控蛋白相互关系的研究

目的　了解雄激素受体 (AR)、雌激素受体 (ER)在病理性瘢痕中的表达及其与细胞周期调节蛋白D1(cyclinD1)、p16之间的相互关系 ,以探讨他们在瘢痕形成过程中的作用及机制。方法　采用免疫组化方法 (SP法 )对 30例瘢痕标本进行研究 ,以正常皮肤组织为对照 ,观察上述指标的表达。结果　正常皮肤及普通瘢痕成纤维细胞中所有指标均为阴性 ;增生性瘢痕与瘢痕疙瘩成纤维细胞中cyclinD1、p16、AR与正常皮肤相比差异均有显著性意义 (P <0 0 5 ) ;瘢痕疙瘩成纤维细胞cyclinD1和AR的表达高于增生性瘢痕 ,且有显著性意义 (P <0 0 5 ) ;p16在瘢痕疙瘩成纤维细胞的表达比增生性瘢痕为高 ,但两者之间差异无显著性意义。在病理性瘢痕中cyclinD1和AR的表达具有明显的相关性。结论　AR在病理性瘢痕的发生及发展中起一定的作用 ,它可能是通过与其配体结合后促使与cyclinD1有关的基因表达而发挥作用的。在瘢痕疙瘩里可能存在cyclinD1的促细胞增生作用超过P16细胞抑制 ,所以细胞呈现持续增殖状态 ;而在增生性瘢痕里cyclinD1与p16可能处于相对的平衡状态 ,细胞生长具有一定的自限性。     

Fibronectin gene expression differs in normal and abnormal human wound healing

The overproduction of fibronectin and type I collagen in keloids and hypertrophic scars implicates altered regulation of extracellular matrix components as an important aspect of these wound healing pathologies. However, little is known about the similarities and differences in extracellular matrix gene expression during normal and abnormal wound healing. This study compared the content of fibronectin messenger RNA and rates of fibronectin protein biosynthesis in fibroblasts derived from normal skin, normal scar, keloid, and hypertrophic scar. Fibronectin expression was enhanced in cells from both normal and abnormal wounds relative to cells from quiescent normal skin. Matched pairs of normal and keloid fibroblasts from the same individuals were also compared, and three of the four pairs showed higher fibronectin expression by the keloid cells at the levels of messenger RNA and protein synthesis. This was consistent with previous studies showing elevated steady state content of fibronectin in keloid cells relative to normal cells from the same individual. Fibronectin messenger RNA and protein content in the tissues from which these cells were derived was examined by in situ hybridization and immunohistochemistry. These studies revealed that in vivo, the steady state content of fibronectin messenger RNA and protein was highest in abnormal wounds, less in most normal scars, and lowest in normal skin. Thus, fibroblasts from keloids and hypertrophic scars overexpressed fibronectin in vivo relative to normal skin and normal scar and retain this characteristic in vitro relative to normal skin. Although normal scars contained little fibronectin protein and messenger RNA, cultured fibroblasts derived from these scars had contents of fibronectin messenger RNA and rates of biosynthesis in vitro similar to those of keloid fibroblasts. This indicates that the fibronectin regulatory pathway in scar fibroblasts is influenced by the tissue environment. These results are discussed with respect to the relationship of fibronectin expression in keloids, hypertrophic scars, and normal wounds in human beings.     

Wide spread scars, hypertrophic scars, and keloids

Patients with a wide scar may complain of having a "keloid," yet have a hypertrophic or a wide spread scar. The plastic surgeon should make the appropriate clinical diagnosis, because therapy varies depending on the condition present. A wide spread scar is best treated with excision and closure. A buried dermal flap may help to prevent recurrence, which is nevertheless likely to some degree. A hypertrophic scar can be distinguished from a keloid on clinical grounds. Although both may be red, nodular, and itchy, the keloid overgrows the original wound boundary and is much more likely to recur after surgical excision. Nonsurgical treatment of hypertrophic scars and keloids is similar, using repeated intralesional injections of Kenalog 40 mg per cc and sustained pressure on the lesion when possible. Surgical treatment differs for hypertrophic scars or keloids. Scar excision and closure, and selective Z-plasty, may be used in hypertrophic scars. In keloids, aggressive surgery is usually avoided, unless the lesion has a narrow pedicle. Surgery of keloids should be accompanied by intra- and postoperative Kenalog-40 injections, and on occasion by sustained pressure. Very large keloids may be resistant to medical management, and too aggressive for surgery owing to a high likelihood of recurrence. These difficult lesions serve as the impetus for continued biochemical and tissue culture research, seeking a biochemical means of control keloids.     

Detection of apoptosis in keloids and a comparative study on apoptosis between keloids, hypertrophic scars, normal healed flat scars, and dermatofibroma

Recent studies have suggested that the regulation of apoptosis during wound healing is important in scar establishment and the development of pathological scarring. In this study, we demonstrate that keloid fibroblasts can be identified as apoptotic cells because of their highly condensed chromatin and discrete nuclear fragments. To further reveal the phenomenon of apoptosis, we quantified the number of terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in surgically resected tissues of keloids (N = 10), hypertrophic scars (N = 10), normal healed flat scars (N = 10), and dermatofibroma (N = 10). The number of TUNEL-positive cells was relatively low, but was significantly higher for the keloid group compared with the normally healed flat scar group (p = 0.004), suggesting reduced cell survival and increased apoptotic cell death in a subpopulation of keloid fibroblasts. Furthermore, the number of TUNEL-positive cells was significantly higher for the keloid group compared with the dermatofibroma group (p = 0.044), suggesting that a subpopulation of keloid fibroblasts may suppress tumorgenicity at a greater rate than dermatofibroma by undergoing cell death. Hypertrophic scars had significantly higher levels of apoptosis than normally healed flat scars (p = 0.033). Therefore, these results suggest that selected fibroblasts in keloids and hypertrophic scars undergo apoptosis, which may play a role in the process of pathological scarring.     

Study of microvascular structure in keloid and hypertrophic scars: density of microvessels and the efficacy of three-dimensional vascular imaging

We have investigated the blood vessels in keloids and hypertrophic scars, both morphologically and statistically. We also tried to construct three-dimensional images of blood vessels in a keloid and hypertrophic scar to clarify the vascular patterns. Keloids (n = 16) and hypertrophic scars (n = 12) were stained with haematoxylin and eosin, and immunostained with anti-CD31 antibody. The capillary density (number/1.0 mm(2)) and length of the major and minor axes were measured, and the major:minor axis ratio was calculated. Eighty serial sections were prepared from the preparations. Using image preparation software (Realia, INTAGE), the 80 input images were superimposed to construct a three-dimensional image of blood vessels in the tissue. We initially succeeded in constructing three-dimensional images of blood vessels in a keloid and hypertrophic scar. By statistical analysis of the vascular density and morphology, we clarified that there were fewer capillaries in keloids than in hypertrophic scars (p < 0.01), and that the vascular lumen was flattened. Capillaries in the central region of keloids tended to flat, compared with those in the marginal region. Three-dimensional images suggested that there was no microvascular communication in keloids; there was also an inadequate blood supply in keloid tissue. These findings may be a result of the growth of collagen and fibroblasts with keloid maturation.     

整合素α5β1在病理性瘢痕中的表达及意义

目的　研究整合素α5β1 在病理性瘢痕中的表达情况 ,探讨其在瘢痕发生、发展中的作用和意义。方法　运用SP免疫组化及SPA 胶体金免疫电镜技术对 15例增生性瘢痕、15例瘢痕疙瘩及 10例正常皮肤进行整合素α5β1 的检测 ,并对结果进行半定量及定量分析。结果　在瘢痕疙瘩和增生性瘢痕的成纤维细胞中整合素α5β1 呈阳性表达 ,较正常皮肤强 (P <0 0 1) ;在瘢痕疙瘩中的表达较增生性瘢痕强 (P <0 0 1)。结论　整合素α5β1 与病理性瘢痕发生、发展关系密切。设法减少整合素α5β1 在成纤维细胞的过度表达或许是抑制瘢痕增生、软化瘢痕的新途径     

Study of microvascular structure in keloid and hypertrophic scars: Density of microvessels and the efficacy of three-dimensional vascular imaging

Abstract

We have investigated the blood vessels in keloids and hypertrophic scars, both morphologically and statistically. We also tried to construct three-dimensional images of blood vessels in a keloid and hypertrophic scar to clarify the vascular patterns. Keloids (n = 16) and hypertrophic scars (n = 12) were stained with haematoxylin and eosin, and immunostained with anti-CD31 antibody. The capillary density (number/1.0 mm²) and length of the major and minor axes were measured, and the major:minor axis ratio was calculated. Eighty serial sections were prepared from the preparations. Using image preparation software (Realia, INTAGE), the 80 input images were superimposed to construct a three-dimensional image of blood vessels in the tissue. We initially succeeded in constructing three-dimensional images of blood vessels in a keloid and hypertrophic scar. By statistical analysis of the vascular density and morphology, we clarified that there were fewer capillaries in keloids than in hypertrophic scars (p < 0.01), and that the vascular lumen was flattened. Capillaries in the central region of keloids tended to flat, compared with those in the marginal region. Three-dimensional images suggested that there was no microvascular communication in keloids; there was also an inadequate blood supply in keloid tissue. These findings may be a result of the growth of collagen and fibroblasts with keloid maturation.     

皮质类固醇在增生性瘢痕和瘢痕疙瘩患者治疗中的应用效果

探讨在临床中运用皮质类固醇治疗增生性瘢痕和瘢痕疙瘩的效果。方法 应用回顾性分析 方法，选取我院在2022年5月-2023年5月收治的50例增生性瘢痕和瘢痕疙瘩患者为研究对象，根据治疗方 法的不同分为对照组和观察组，各25例。对照组采用常规瘢痕疙瘩切除手术，观察组采用瘢痕疙瘩切除手 术联合皮质类固醇药物治疗，比较两组临床疗效、瘢痕改善情况。结果 观察组治疗总有效率为92.00%，高 于对照组的64.00%（P＜0.05）；观察组皮肤色泽、瘢痕柔软度、瘢痕厚度以及周围血管分布评分均低于对 照组（P ＜0.05）。结论 在对临床增生性瘢痕和瘢痕疙瘩患者治疗中，运用皮质类固醇药物进行治疗，可 提高患者的临床疗效，改善瘢痕情况，安全性良好。     

病理性瘢痕裸鼠模型的建立

目的 验证所构建裸鼠瘢痕疙瘩和增生性瘢痕模型在病理性瘢痕研究中的可行性。方法 将0．8cm×0．8cm×0．5cm的人瘢痕疙瘩和增生性瘢痕组织块移植到裸鼠皮下，大体观察裸鼠及植入物情况。移植后第16天取出移植物与原标本进行下列指标的比较：体积、瘢痕的镜下特征、酸性黏多糖含量及Ⅰ、Ⅱ型胶原含量。结果 移植后裸鼠全部存活且创面愈合良好。瘢痕疙瘩、增生性瘢痕组织块的酸性黏多糖含量移植前分别为3448±1452、1940±509，移植后分别为3237±1871、1809±552，移植前后比较，差异无统计学意义（P〉0．05）。植入物保持着原有的胶原特性及含量，未检测到细胞变性坏死。结论 增生性瘢痕和瘢痕疙瘩以适当体积移植到裸鼠皮下，其生物学特性可在一定时间内保持稳定，该动物模型适用于病理性瘢痕的临床研究。     

Molecular dissection of abnormal wound healing processes resulting in keloid disease

Keloids are locally aggressive scars that typically invade into healthy surrounding skin and cause both physical and psychosocial distress to the patient. These pathological scars occur following minimal skin trauma after a variety of causes including burns and trauma. Although the pathogenesis of keloid disease is not well understood, it is considered to be the end product of an abnormal healing process. The aim of this review was to investigate the molecular and cellular pathobiology of keloid disease in relation to the normal wound healing process. The molecular aberrances in keloids that correlate with the molecular mechanisms in normal wound healing can be categorized into three groups: (1) extracellular matrix proteins and their degradation, (2) cytokines and growth factors, and (3) apoptotic pathways. With respect to cellular involvements, fibroblasts are the most well‐studied cell population. However, it is unclear whether the fibroblast is the causative cell; they are modulated by other cell populations in wound repair, such as keratinocytes and macrophages. This review presents a detailed account of individual phases of the healing process and how they may potentially be implicated in aberrant raised scar formation, which may help in clarifying the mechanisms involved in keloid disease pathogenesis.     

A new surgical treatment of keloid: keloid core excision

Keloids and hypertrophic scars result from excessive collagen deposition, the cause of which is not yet known. Unlike hypertrophic scars, keloids frequently persist at the site of injury, often recur after excision and always overgrow the boundaries of the original wound. There have been many trials to control keloids, but most of them have been unsuccessful. The authors propose a new surgical technique to treat keloids and name it keloid core extirpation. They excise the inner fibrous core from the keloid and cover the defect with a keloid rind flap, which is arterialized by the subcapsular vascular plexus. The authors treated 24 keloids of the ear, trunk, face, and genitalia with keloid core excision. Four cases of partial rind flap congestion or necrosis occurred. Those patients who healed primarily after surgery showed no evidence of keloid recurrence as long as they were followed. The authors have found the keloid core extirpation technique to be excellent in preventing keloid recurrence, with no adjuvant therapy after surgery.     

Hydration and occlusion treatment for hypertrophic scars and keloids.

In 31 patients with hypertrophic scars or keloids, a side by side test was carried out to check the efficacy of an occlusive dressing technique using cream which did not contain silicone oil, versus a simple application of vaseline, used as a control. In all cases, the cream treated areas of scar and keloid demonstrated a remarkable improvement over that of the vaseline treated area. These findings strongly suggest that the mechanisms of hydration and occlusion are the main basis of the therapeutic action of this method in treating hypertrophic scars and keloids.     

Intra-lesional injections of collagenase are ineffective in the treatment of keloid and hypertrophic scars.

The treatment of keloid and hypertrophic scars remains difficult. Enzymatic digestion of keloid scars has been previously proposed as an effective treatment strategy for reducing the volume of keloid scars. To test this, we administered intra-lesional injections of pure collagenase (between 600 and 4500 units for each scar) into the keloid and hypertrophic scars of seven human volunteers (five keloid and two hypertrophic scars). Five patients (three keloid and two hypertrophic) received more than one injection of collagenase. The treatment resulted in a temporary reduction in scar volume for three of the patients with keloid scars. However, scar volumes for these three patients returned to the same (or greater) levels after 6 months of follow-up. Treatment with collagenase produced no change in scar volume for the two patients with hypertrophic scar. Side effects were numerous and severe including; pain, swelling, blistering, ulceration and ecchymosis at the site of injection. One patient required admission to hospital for 48 h after the first injection. Maximum length of follow-up was 6 months. None of the seven patients completed the study and returned for final follow-up at 2 years. This pilot study suggests that treatment of keloid and hypertrophic scars with intra-lesional injections of collagenase is ineffective.     

Nonsurgical Management of Hypertrophic Scars: Evidence-Based Therapies,Standard Practices,and Emerging Methods

Hypertrophic scars, resulting from alterations in the normal processes of cutaneous wound healing, are characterized by proliferation of dermal tissue with excessive deposition of fibroblast-derived extracellular matrix proteins, especially collagen, over long periods, and by persistent inflammation and fibrosis. Hypertrophic scars are among the most common and frustrating problems after injury. As current aesthetic surgical techniques become more standardized and results more predictable, a fine scar may be the demarcating line between acceptable and unacceptable aesthetic results. However, hypertrophic scars remain notoriously difficult to eradicate because of the high recurrence rates and the incidence of side effects associated with available treatment methods. This review explores the various treatment methods for hypertrophic scarring described in the literature including evidence-based therapies, standard practices, and emerging methods, attempting to distinguish those with clearly proven efficiency from anecdotal reports about therapies of doubtful benefits while trying to differentiate between prophylactic measures and actual treatment methods. Unfortunately, the distinction between hypertrophic scar treatments and keloid treatments is not obvious in most reports, making it difficult to assess the efficacy of hypertrophic scar treatment.     

Clinical and histologic effects from CO2 laser treatment of keloids

Keloids and hypertrophic scars are abnormal responses to wound healing. In general, keloids exhibit a proliferative growth beyond the margins of the scar and remain persistent; while hypertrophic scars are contained to the original wound and may regress over time. In particular, keloid formation is one of the most challenging clinical problems, with increasing frequency in surgical practice. Many treatments are available such as intralesional corticosteroids, topical applications, cryotherapy, surgical excision, radiation therapy, silicone gel sheeting, pressure therapy, and laser therapy. There are no set guidelines for the treatment of keloids and the most common treatments are individualized and depended on the distribution, size, thickness, and consistency of lesions. The authors have evaluated carbon dioxide laser successfully in the treatment of keloids and the aim of this study was to determine the immediate and long-term histologic and clinical effects of keloids after carbon dioxide laser. Fifty consecutive patients (40 females, 10 males, ages 18–60 years, mean age 40 years) with moderate to severe keloids were evaluated. All the patients received regional treatments (deltoid, elbow, chin, and ear) in an outpatient setting with a high-energy pulsed CO₂ laser. Significant immediate and prolonged clinical improvement in skin tone, texture, and appearance of carbon dioxide laser was examined in all patients. Dermal remodeling was observed also on histologic examination of biopsied tissue after treatment. Carbon dioxide laser appears to be effective and well tolerated for the treatment of keloids, avoiding the adverse effects and lengthy recovery time.     

病理性瘢痕中原癌基因c-myc和c-fos的表达

目的　探讨原癌基因的表达与病理性瘢痕形成的相关性。方法　应用免疫组化SP法 ,检测c -myc和c -fos蛋白在增生性瘢痕、瘢痕疙瘩和正常皮肤组织中的表达和分布 ,并用图像定量分析比较其差异。结果　在增生性瘢痕和瘢痕疙瘩的成纤维细胞中c-myc、c -fos呈强阳性表达 ,两组间无明显差异 ,而与正常皮肤对照组均有显著性差异。结论　增生性瘢痕与瘢痕疙瘩中c -myc、c -fos蛋白表达升高 ,存在c -myc和c -fos原癌基因的激活 ,可能参与了成纤维细胞的分化增殖或表型转化、胶原合成与降解以及对细胞因子的调控 ,并导致瘢痕增生。     

Postoperative radiation protocol for keloids and hypertrophic scars: statistical analysis of 370 sites followed for over 18 months

BACKGROUND: Before 2002, keloids and intractable hypertrophic scars were treated at our facility with postoperative irradiation of 15 Gy (the traditional protocol). Analysis of the therapeutic outcomes of patients treated with this protocol showed that the recurrence rates of keloids and intractable hypertrophic scars in the anterior chest wall, as well as the scapular and suprapubic regions, were statistically higher than at other sites, while the recurrence rates in earlobes were lower. Thus, we customized doses for various sites. This report describes our trial of postoperative radiation therapy. METHODS: Between January 2002 and September 2004, 109 patients with 121 keloid and intractable hypertrophic scar sites were treated with surgical excision following the new protocol: electron-beam irradiation at total doses of 10, 15, or 20 Gy, depending on the site. The recurrence rates and toxicities were historically followed in 218 patients with 249 keloid and intractable hypertrophic scar sites treated with the old protocol of surgical removal followed by irradiation at 15 Gy (without variation by site). The minimal follow-up time was 18 months. Statistical analysis was performed using Fisher exact probability test. RESULTS: Total recurrence rates were 29.3% before 2002 and 14.0% after 2003. The recurrence rate in the anterior chest wall was statistically reduced. Outcomes of earlobe did not differ between irradiation with 15 Gy or 10 Gy. CONCLUSIONS: Keloids and intractable hypertrophic scars should be treated with dose protocols customized by site. Our results suggest that keloid and intractable hypertrophic scar sites with a high risk of recurrence should be treated with 20 Gy in 4 fractions over 4 days and that earlobe should be treated with 10 Gy in 2 fractions over 2 days.     

A wound contraction experimental model for studying keloids and wound-healing modulators

Preventing and treating hypertrophic and keloid scars is difficult because of the lack of knowledge about their genesis. Tissue repair can be studied with biocompatible matrices and ex vivo cultures of different cell types. We used an experimental model where collagen gels populated by human fibroblasts underwent progressive contraction, allowing the study of wound healing remodeling. The fibroblast-populated lattices showed the greater contraction of the gel populated by fibroblasts from keloids versus fibroblasts from normal skin. Moreover, fibroblast growth factor (FGF) and transforming growth factor beta (TGF-beta) involved in scar formation were added to the collagen gels populated by normal skin fibroblasts. TGF-beta caused an increase in gel contraction; FGF did not. The mean percentages of contraction of the gels populated by keloid fibroblasts were very similar to the percentages of gels populated by normal skin fibroblasts with added TGF-beta. These observations confirm the existing hypothesis that TGF-beta may be involved in keloid formation.     

Effect of TGF-beta2 on proliferative scar fibroblast cell kinetics.

Keloids, hypertrophic scars, and burn hypertrophic scars are all forms of proliferative scarring characterized by overabundant matrix formation. Recently these dermal proliferative disorders have been linked clinically to the cytokine transforming growth factor beta (TGF-beta), and in vitro tests have shown it to be responsible for the activation of fibroblasts and their production and deposition of collagen. Using an established in vivo animal model of proliferative scarring, the effects of this cytokine, specifically the isoform TGF-beta2, on these scars were examined. Proliferative scar specimens were implanted into athymic, asplenic nude rats and isolated in sandwich island flaps based on the superficial inferior epigastric pedicle. After establishment of the transferred flap, the scars were injected with varying doses of TGF-beta2 or vehicle for 5 consecutive days and then again on days 10, 15, and 20. The specimens were measured weekly during the period of dosing, and a biopsy was acquired on days 30 and 60. Fibroblasts from the explanted biopsies and the original scars were grown in cell culture, and cell proliferation studies were performed and the results compared. There was a dose response to TGF-beta2, with 200 ng showing the greatest effect. From the original scar specimens, keloid scars demonstrated the greatest cell proliferation kinetics--significantly faster than nonburn and burn hypertrophic scars. After treatment with TGF-beta2, both keloids and burn hypertrophic scars showed an increase in their cell proliferation kinetics compared with vehicle alone. This was not demonstrated with the nonburn hypertrophic scars. Elevated levels of TGF-beta2 are a major contributing factor to the process of proliferative scars, but because nonburn hypertrophic scars do not result in an equally increased response to this cytokine, a truly causative role for this cytokine cannot be promulgated. Rather, it is the combination of the proliferative scar fibroblasts' abnormal response to TGF-beta2 stimulation and elevated levels of this cytokine that controls more accurately the process of keloid and burn hypertrophic scar formation.