瘢痕疙瘩发病机制的研究

瘢痕疙瘩是一种以侵袭性生长为特点的良性肿瘤。瘢痕疙瘩有一定的遗传易感性,瘢痕疙瘩患者多有家族倾向性及家族聚集性,属于常染色体显性遗传。皮肤创伤愈合过程中受多种细胞因子,信号传导通路,细胞外基质的影响下,成纤维细胞的过度增殖和细胞外基质中胶原的沉积而导致瘢痕疙瘩的形成。近年来,很多学者通过分子生物学研究得出瘢痕疙瘩形成过程中各种基因作用机制及细胞因子的表达异常,对瘢痕疙瘩的诊断及治疗提供了一个新方向。     

MMP-2在瘢痕疙瘩侵袭中的作用研究进展

瘢痕疙瘩是一种常见的皮肤病,基质金属蛋白酶-2（MMP-2）作为调节细胞外基质平衡的主要酶,在瘢痕疙瘩的发病尤其是侵袭生长中起着重要作用,其机制可能是通过降解胶原束边缘的细胞外基质而使成纤维细胞向周围正常组织侵袭。     

皮损内注射治疗瘢痕疙瘩的研究进展

瘢痕疙瘩是一种以皮肤结缔组织增生和侵袭性生长为主要特征的病理性瘢痕。多在外伤、炎症、手术后形成,好发于胸前、肩胛部、耳垂等部位。暴露部位瘢痕疙瘩影响美观,功能区皮损影响局部活动,且瘢痕疙瘩常伴瘙痒、疼痛、局部过度敏感等,对患者造成沉重心理负担,严重者生活质量受到影响。虽然瘢痕疙瘩在临床上治疗方法多样,但因其形成机制尚不明确,复发率高,故是外科治疗的难题。皮损内注射治疗已广泛应用于国内外瘢痕疙瘩的治疗,本文对其作以综述。     

血小板衍化生长因子受体蛋白在瘢痕疙瘩中的表达

目的 探讨血小板衍化生长因子受体(PDGFR)-α和-β在瘢痕疙瘩组织和瘢痕疙瘩来源成纤维细胞中的表达及其在瘢痕疙瘩发病中的作用.方法 应用免疫组化法检测15份瘢痕疙瘩和10份正常人皮肤标本PDGFR-α和-β蛋白的分布.体外原代培养成纤维细胞和蛋白质印迹法检测PDGFR蛋白的表达.结果 在瘢痕疙瘩组织中PDGFR-β表达明显增高,而PDGFR-α在瘢痕疙瘩中的表达似与瘢痕疙瘩的临床生长状态有关.在边缘充血、浸润生长明显的皮损,PDGFR-α呈强烈表达;而在边缘稳定、无明显浸润态势之皮损,PDGFR-α呈低表达.体外培养的成纤维细胞中,PDGFR-α比PDGFR-β表达更为丰富.结论 两种PDGFR的表达增高导致瘢痕疙瘩成纤维细胞对PDGF敏感性提高,决定了PDGF在瘢痕疙瘩发病机制中的作用.     

胃泌素释放肽及其受体在瘢痕疙瘩中的表达和临床意义

目的研究瘢痕疙瘩内胃泌素释放肽(GRP)及其受体(GRPR)的表达,探讨其在瘢痕疙瘩中的作用。方法使用蛋白质印迹分析检测瘢痕疙瘩及正常皮肤组织内的GRP含量,实时定量PCR检测瘢痕疙瘩及正常成纤维细胞上的GRPR表达。结果瘢痕疙瘩的GRP及GRPR表达均较正常表达升高,差异有统计学意义(P<0.05)。结论瘢痕疙瘩的GRP及GRPR过表达可能在瘢痕疙瘩的发生发展过程中有重要作用。     

过表达hsa＿circ＿0005986通过miR-129-5p/ABCB1轴促进宫颈癌细胞的增殖和转移

目的探讨hsa_circ_0005986对人宫颈癌细胞(SiHa细胞)增殖和转移的影响。方法 2021年3月从研域生物技术(上海)有限公司购入人宫颈癌细胞(SiHa细胞)和人正常宫颈上皮细胞(H8细胞)作为研究对象。利用实时荧光定量PCR检测SiHa细胞及人正常宫颈上皮细胞(H8细胞)中hsa_circ_0005986、miR-129-5p和ABCB1的表达量;分别利用CCK-8、细胞侵袭实验和Western blot检测下调hsa_circ_0005986对SiHa细胞增殖、侵袭和上皮间质转化(EMT)的影响。miRanda和双荧光素酶报告基因实验检测hsa_circ_0005986和miR-129-5p之间的关系。下调miR-129-5p表达后,检测SiHa细胞的增殖、侵袭和EMT能力;检测hsa_circ_0005986通过miR-129-5p对SiHa细胞增殖、侵袭和EMT的影响。TargetScan和双荧光素酶报告基因实验检测miR-129-5p与ABCB1之间的关系。siRNA下调ABCB1表达,分析SiHa细胞增殖、侵袭和EMT能力。结果与H8细胞相比,SiHa细胞中hsa_circ_0005986和ABCB1表达上调(P0.01),miR-129-5p表达下调(P0.01)。下调hsa_circ_0005986明显抑制了SiHa细胞增殖、侵袭与EMT;hsa_circ_0005986与miR-129-5p具有靶向关系;上调hsa_circ_0005986通过miR-129-5p促进SiHa细胞增殖、侵袭与EMT。miR-129-5p靶向ABCB1。下调ABCB1表达抑制了SiHa细胞增殖、侵袭与EMT。结论过表达hsa_circ_0005986通过miR-129-5p/ABCB1轴促进SiHa细胞增殖、侵袭及EMT。     

妊娠期瘢痕疙瘩的预防与治疗研究进展

瘢痕疙瘩是一种慢性异常纤维增生性皮肤病,可引起身体功能障碍和外观的缺陷。瘢痕疙瘩的治疗仍是一大难题,目前尚无广泛认可的安全有效治疗方法。研究证实,妊娠可影响瘢痕疙瘩的形成和发展。而妊娠期瘢痕疙瘩的预防和治疗方法有限,本文综述了妊娠期瘢痕疙瘩的特点和其预防和治疗的新进展。     

瘢痕疙瘩及其成纤维细胞p16基因甲基化状态和相关基因表达研究北大核心CSCD

目的 探讨瘢痕疙瘩中成纤维细胞p16基因甲基化在其发生发展中的作用.方法 分离、培养来自瘢痕疙瘩皮损和健康人皮肤原代成纤维细胞;免疫组化法检测瘢痕疙瘩皮损中p16表达情况;实时荧光定量PCR检测瘢痕疙瘩成纤维细胞中p16、DNA甲基转移酶mRNA表达;亚硫酸氢盐修饰后测序（BSP法）检测瘢痕疙瘩皮损及培养的原代成纤维细胞p16基因甲基化状态.结果 瘢痕疙瘩成纤维细胞中p16基因mRNA表达低于健康人皮肤成纤维细胞（相对表达量2-△△Ct分别为0.64±0.18和1.92±0.23,t=10.54,P＜0.05）.瘢痕疙瘩成纤维细胞三种DNA甲基转移酶（DNMT）基因mRNA表达水平（DNMT1、DNMT3A、DNMT3B分别为2.58±0.23、4.87±0.46、1.57±0.12）与健康人皮肤成纤维细胞（分别为1.13±0.21、2.38±0.32、0.57±0.16）相比均存在高表达,两组比较,t值分别为11.22、10.81、12.45,均P＜0.05.瘢痕疙瘩组织和瘢痕疙瘩原代成纤维细胞内p16启动子区甲基化程度分别为1.81％±0.46％和3.15％±0.94％,明显高于健康人皮肤组织（0.90％±0.35％,F=14.23,P＜0.01）和原代成纤维细胞（0.17％±0.29％,F=37.62,P＜0.01）.结论 瘢痕疙瘩成纤维细胞中p16基因甲基化及其低表达与瘢痕疙瘩的失控性生长可能相关,DNA甲基转移酶在其发病中可能起一定作用.     

表观遗传学在瘢痕疙瘩发病中的作用

越来越多的证据表明,表观遗传学与瘢痕疙瘩形成机制可能相关.与正常皮肤相比,瘢痕疙瘩全基因组胞嘧啶?磷酸二酯键鸟苷岛中低甲基化比高甲基化更常见,且相关基因的启动子区亦存在同样现象.启动子的高甲基化通常发生在易感基因的相同位点,甲基化可能起到早期标记物的作用.去乙酰化酶的表达明显增高,活性增强,基因的组蛋白乙酰化修饰水平降低,细胞凋亡下降,最终促进了瘢痕疙瘩的发生发展.miR?21等23种miRNA表达上调,miR?203等9种miRNA表达下调.表观遗传学路径在瘢痕疙瘩的形成和发展中的作用值得进一步研究.     

瘢痕疙瘩发病机制研究进展

瘢痕疙瘩常超出原伤口界限，呈侵袭性生长、瘤样增生，伴痒痛不适，单纯手术切除后易复发，治愈十分困难。目前其机制研究涉及多基因、多细胞、多分子以及多通路，但仍未取得突破性进展。本文就瘢痕疙瘩发病机制进行综述，以期为科学研究及临床治疗提供更多思路。     

成纤维细胞活化蛋白在瘢痕疙瘩组织中的表达及意义

 目的:了解成纤维细胞活化蛋白（FAP）在瘢痕疙瘩组织中的表达情况,探讨FAP在瘢痕疙瘩发病机制中的作用。方法:采用免疫组化染色技术检测30例瘢痕疙瘩组织（病例组）和20例正常皮肤组织（对照组）中FAP的表达强度,并比较两组间及瘢痕疙瘩不同临床分级之间FAP表达阳性率的差异。结果:病例组瘢痕疙瘩组织中FAP在成纤维细胞和血管内皮细胞内表达,阳性率为73.33％;对照组正常皮肤组织中未见FAP表达,两组间FAP表达阳性率比较,差异有统计学意义（  X²=26.19,P=0.001）;瘢痕疙瘩临床分级中,轻度与重度之间及中度与重度之间比较,FAP表达阳性率差异均有统计学意义（P值分别为0.002、0.006）。结论:瘢痕疙瘩组织中FAP表达阳性率明显高于正常皮肤组织;瘢痕疙瘩临床分级越严重,FAP表达阳性率越高;FAP可能参与瘢痕疙瘩的发病机制,针对FAP的干预可能有助于瘢痕疙瘩的治疗。     

Enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP‐1 and Akt pathway in keloids

Please cite this paper as: Enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation: role of MCP‐1 and Akt pathway in keloids. Experimental Dermatology 2010; 19 : e142–e150. Abstract: Keloids are fibrous overgrowth induced by cutaneous injury. The pathogenesis of keloids is poorly understood, and no convincing animal model exists. Current hypotheses of the pathogenesis classify keloids as an entity of aberrant fibrosis. Hyperactivation of the MCP‐1/CCR2 axis reportedly causes fibrosis in liver cirrhosis, atherosclerosis and lung fibrosis. Circulating CD14+ monocytes are precursors of circulating fibrocytes and contribute to fibrogenesis by a MCP‐1/CCR2‐dependent loop. As there is an increase in monocyte lineages in keloids, the aim of this study is to determine whether peripheral CD14+ monocytes in keloid patients trigger fibroblast proliferation through MCP‐1. Expressions of MCP‐1 and its receptor CCR2 in keloid lesions were measured by immunohistochemistry and real‐time PCR. The results revealed an increase in MCP‐1 and CCR2 in the keloid tissues. Co‐culture of keloid CD14+ cells and normal fibroblasts enhanced fibroblast proliferation and a parallel increase in extracellular MCP‐1. We further found that MCP‐1 modest enhanced fibroblast proliferation via Akt activation. Blockade of either MCP‐1 or Akt signaling suppressed the mediation of fibroblast proliferation by CD14+ cells from patients. These results demonstrated that enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation via Akt pathway in keloids. We concluded that enhanced MCP‐1 release by keloid CD14+ cells augments fibroblast proliferation, which might initiate keloid development.     

结缔组织生长因子在瘢痕疙瘩中表达的研究

目的探讨结缔组织生长因子(CTGF)在瘢痕疙瘩发病中的作用。方法应用半定量逆转录聚合酶链反应技术检测30例瘢痕疙瘩患者皮损及对应邻近未受累皮肤中CTGFmRNA的表达,并以15例正常人皮肤组织作为对照。同时应用SP免疫组化技术对5例瘢痕疙瘩组织和5例正常人皮肤标本进行了检测。结果CTGFmRNA在瘢痕疙瘩及其边缘正常皮肤中的表达均明显高于正常人对照,差异有显著性(P<0.01)。瘢痕疙瘩CTGF的表达高低与病程无相关性(P>0.05)。免疫组化研究证实CTGF在瘢痕疙瘩中呈强表达,而在正常人皮肤中无表达。在瘢痕疙瘩组织边缘,CTGF表达呈现由强至弱的过渡现象。结论CTGF在瘢痕疙瘩中持续高度表达,提示其与瘢痕疙瘩的慢性纤维化有关。CTGF可能成为临床治疗瘢痕疙瘩的一个有力靶位。     

Treg‐enriched CD4+ T cells attenuate collagen synthesis in keloid fibroblasts

Keloid is an inflammatory and fibrotic disease with an unknown pathogenesis. Regulatory T cells (Tregs) of CD4+ lineage can suppress other effector CD4+ T cells and modulate the immune response. A relative decrease in the number of Tregs may be involved in the pathogenesis of inflammatory and fibrotic diseases. We therefore investigated the number of Tregs in keloids using immunohistochemistry and examined the interaction between Tregs and keloid fibroblasts (KFs) using a coculture system. It was found that the ratio of Tregs/CD4+ T cells was lower compared with that in other common inflammatory skin conditions. In addition, Treg‐enriched CD4+ T cells reduced collagen synthesis by KFs. Our findings suggest that a local imbalance of Tregs contributes to the development of keloids and that correction of this imbalance might represent a novel therapeutic approach to keloid fibrosis.     

瘢痕疙瘩发病机制及术后放疗研究进展

目前研究表明遗传、伤口张力、感染、内分泌因素等均可导致瘢痕疙瘩的发生和发展。单一治疗瘢痕疙瘩的效果不能令人满意，应多种方法联合治疗，手术切除联合放疗是治疗瘢痕疙瘩较有效的方案之一。本文就近年来瘢痕疙瘩的发病机制及术后放疗作一综述。     

Bilateral breast keloids in an elderly woman associated with bilateral breast cancers and high concentration of serum tumor growth factor‐β

We report a case of bilateral annular breast keloids in a 72‐year‐old woman who had been suffering from bilateral breast cancers. Histopathologically, the keloids showed unique distribution of α‐SMA+, CD34? myofibroblasts and α‐SMA?, CD34+ fibroblasts depending on the region. High serum levels of tumor growth factor‐β were detected at 6 months after the development of the breast keloids, but not at 10 months. CD163‐positive cells were abundantly detected in the skin of the elevated portion of the keloids. In contrast, these cells were considerably less numerous in the skin of the central healing portion compared with the skin of the elevated expanding portion. One interesting idea based on these results is that high levels of tumor growth factor‐β released from CD163‐positive cells played a crucial role in the formation of breast keloids through active induction of fibroblast differentiation into myofibroblasts. The present case strongly supports the previously proposed idea that keloids can form as a paraneoplastic phenomenon in breast cancer patients with keloid constitution.     

瘢痕旁和瘢痕下扩张器埋植治疗17例胸部瘢痕疙瘩

目的 探讨瘢痕旁和瘢痕下扩张器埋植治疗前胸部大面积瘢痕疙瘩的疗效。方法 从2006年3月至2009年6月,17例前胸部大面积瘢痕疙瘩患者共接受21个扩张器埋植。瘢痕面积最大15.7 cm × 5.5 cm,最小4.5 cm × 3.0 cm。其中瘢痕旁埋植12个,瘢痕下埋植9个。瘢痕旁埋植扩张器容量70 ~ 400 ml,瘢痕下埋植80 ~ 500 ml。经6 ~ 8周注水扩张后,行瘢痕疙瘩切除、扩张器取出和扩张皮瓣转移术,同时给予术中即时皮内注射复方倍他米松注射液、术后浅表电子束照射联合治疗,随访12 ~ 50个月。结果 除1个扩张器瘢痕下埋植后感染导致提前取出手术失败外,余20个扩张器均顺利完成整个治疗过程。主要并发症为扩张器外露4个,其中瘢痕旁1个,瘢痕下埋植3个,但未影响二期手术。扩张不满意2个,其中瘢痕旁和瘢痕下各1个。除2例复发外,余15例自觉症状均明显缓解,效果满意。2例复发患者均为扩张不满意,缝合时切口张力较大、且术后延期拆线者。结论 瘢痕旁和瘢痕下扩张器埋植为治疗前胸部大面积瘢痕疙瘩的较为理想的选择方法。切口缝合的张力是决定瘢痕疙瘩术后是否复发的关键。     

Collagen gene expression in keloids: analysis of collagen metabolism and type I, III, IV, and V procollagen mRNAs in keloid tissue and keloid fibroblast cultures

Regulation of collagen gene expression was studied in keloids and fibroblast cultures established from keloid biopsies from 9 patients. The collagen concentration in keloid tissue was not different from that in normal skin. The activities of 2 enzymes catalyzing intracellular collagen biosynthesis, prolyl 4-hydroxylase (PH) and galactosylhydroxylysyl glucosyltransferase (GGT) were significantly elevated in the keloids, the mean increase in the former enzyme being 5-fold and in the latter 3-fold with respect to the controls. The mean procollagen production rate in the keloid fibroblasts was at the control level, with only 1 keloid cell line showing a procollagen synthesis rate higher than the mean value + 2 SD of the controls. The mean PH and GGT activities of the keloid fibroblasts were not elevated, but PH activity in 2 cell lines and GGT activity in 1 cell line were higher than the mean + 2 SD for the controls. Cellular type I, III, IV, and V procollagen mRNAs were measured by slot blot hybridization using specific human cDNA clones for the various collagen types. The amounts of type I, III, and V procollagen mRNAs corresponded to the ratios in which these collagen types are produced by fibroblasts. No synthesis of type IV procollagen mRNA by keloid fibroblasts was observed. The total amount of type I and III procollagen mRNAs correlated significantly (p less than 0.01) with the procollagen synthesis rate measured after radioactive labeling of the cells in the keloid and control fibroblasts, indicating that collagen production in these cells is mainly controlled by regulating the final steady state levels of collagen mRNA. The results suggest that fibroblasts isolated from keloids often synthesize normal amounts of collagen.     

Reduced hyaluronan in keloid tissue and cultured keloid fibroblasts

Extracellular matrix hyaluronan is prominent during wound healing, appearing at elevated levels early in the repair process. It is prevalent throughout the course of fetal wound healing, which is scar-free, but decreases late in adult wound repair, that is often marked by scarring. To determine whether aberrant hyaluronan metabolism is associated with the excessive scarring that characterizes keloids, cultured fibroblasts derived from keloids and from the dermis of normal human skin and scar were compared. Levels of hyaluronan in 48 h conditioned media of keloid-derived cultures were significantly lower than in cultures of normal skin and scar fibroblasts. Profiles of hyaluronan polymer size were comparable in these two cell types, suggesting that excessive hyaluronan degradation was not involved. Hydrocortisone decreased hyaluronan levels approximately 70% in the conditioned media of both keloid and normal fibroblasts. Diminished hyaluronan accumulation in keloid-derived cells compared with normal fibroblasts was also observed in an in vitro wound healing model. Histolocalization of hyaluronan in keloids, normal skin, and scar samples confirmed the biochemical observations that the dermis of keloids, which comprises most of the scar tissue, contained markedly diminished levels of hyaluronan. Alterations in hyaluronan in the epidermis overlying keloids, however, were also observed. A modest increase in hyaluronan staining intensity was observed in the epidermis of keloids, as well as changes in the patterns of distribution within the epidermis, compared with that in normal skin and scar. Increased hyaluronan was present in the granular and spinous layers of the keloid epidermis Abnormalities are present apparently in both the overlying epidermis as well as in the dermis of keloids. Aberrations in signaling between keloid stroma and keloid epidermis may underlie abnormalities that contribute to the excessive fibrosis characteristic of these lesions.