局限性硬皮病发病机制的研究进展

局限性硬皮病是一种以局部皮肤及皮下组织纤维化为特征的疾病.病因不明,发病机制可能涉及小血管的损伤、T细胞的活化以及结缔组织生成增加等多个过程.T细胞活化释放各种细胞因子,趋化因子,主要包括肿瘤坏死因子α、转化生长因子β、可溶性白细胞介素受体2和可溶性白细胞介素受体6等.血管内皮细胞的损伤也可介导纤维化相关的细胞因子释放.局限性硬皮病和系统性硬皮病在发病机制上有一定的区别和联系,概述局限性硬皮病发病机制的最新进展.     

局限性硬皮病的诊治概述

局限性硬皮病（localized scleroderma,LS）也称为硬斑病（morphea）,是一种以局限性皮肤及皮下组织纤维化为特征的疾病。病因未明,可能与多种因素有关。其发病机制涉及血管改变、免疫系统活化和失调、成纤维细胞活化和纤维化,与血管内皮细胞受损、     

系统性硬皮病与组织纤维化

系统性硬皮病(SSC)的病因与发病机制尚未明了,目前认为在基因易感性基础上,由于环境因素刺激而激活机体免疫系统,进而造成血管内皮损伤、成纤维细胞增殖、胶原蛋白及细胞外基质合成与沉积,导致组织纤维化的发生.而组织纤维化的发生与组织微环境改变有关,在众多导致组织微环境改变的因素中,转化生长因子-β、结缔组织生长因子、内皮素-1、角质形成细胞生长因子、白介素-4和γ-干扰素等细胞因子起重要的作用.     

血管病变在系统性硬皮病发病机制中作用的研究进展

系统性硬皮病是以皮肤硬化和内脏器官纤维化为主要表现的自身免疫病,病因与发病机制不明,病理基础为血管病变、免疫异常激活及组织纤维化等.越来越多的研究表明,血管病变可能是系统性硬皮病发病的始发事件,包括小血管痉挛、内膜增生和血管减少等.概述近年来系统性硬皮病相关血管病变的研究进展,包括促血管新生因子(如血管内皮生长因子、基质细胞衍生因子1)和抗血管新生因子(如内皮抑素、正五聚蛋白3)及其受体(如血管内皮生长因子受体和尿激酶型纤溶酶原激活物受体)的紊乱、血管内皮祖细胞和血管内皮细胞数量和功能的异常、血管紧张性的调节失衡以及血小板及其释放物的功能异常等方面.     

血管内皮生长因子在尖锐湿疣中的表达及其意义

目的 探讨尖锐湿疣组织中血管内皮生长因子的表达及其意义.方法 用免疫组化法检测血管内皮生长因子在30例尖锐湿疣组织和10例正常上皮组织中的表达.结果 血管内皮生长因子在尖锐湿疣中表达水平高于正常上皮组织(P<0.05).结论 尖锐湿疣的发生、发展与血管内皮生长因子的异常表达有关.     

Notch信号通路在婴儿血管瘤发病机制中的作用

婴儿血管瘤是婴幼儿最常见的良性肿瘤,目前有关婴儿血管瘤增殖和消退的机制尚未明确,仅局限于婴儿血管瘤形成的分子机制研究.多认为婴儿血管瘤的发生与血管内皮细胞异常增殖及碱性成纤维细胞生长因子、血管内皮细胞生长因子等细胞因子的异常表达有关.近年研究提示,Notch信号通路在婴儿血管瘤发生发展中发挥重要作用.Notch信号刺激血管内皮生长因子,通过调节血管内皮生长因子及其受体,调控血管内皮细胞增殖,参与婴儿血管瘤增生和退化.明确Notch信号在婴儿血管瘤发生机制中的作用,将为婴儿血管瘤提供合理的治疗方向.     

转化生长因子-β、内皮素-1及血管紧张素Ⅱ与硬皮病纤维化关系研究进展

硬皮病的发病机制比较复杂,认为主要与免疫失常相关.研究证实许多细胞因子在其纤维化发病过程中发挥重要作用,目前研究较多的有转化生长因子(TGF)-β、内皮素(ET)-1及血管紧张素(Ang)Ⅱ等.该文综述了上述细胞因子在硬皮病纤维化过程中的作用及相互作用.     

血管内皮生长因子和皮肤肿瘤

血管内皮生长因子是一高度特异的血管内皮细胞有丝分裂原 ,最重要的促血管生长因子之一 ,调节生理性和病理性血管生成。血管内皮生长因子受体特异性地分布于血管内皮细胞表面 ,具有酪氨酸激酶活性。血管内皮生长因子及其受体在皮肤肿瘤中表达 ,并与皮肤肿瘤的发生、发展、转移以及判断皮肤肿瘤的良恶性有关 ,抑制血管内皮生长因子为皮肤肿瘤的治疗开辟新的途径     

细胞因子与真皮纤维化

转化生长因子β和血小板衍生的生长因子等细胞因子作为重要递质,介导了成纤维细胞迁移、增殖和细胞外基质成分的合成,参与了纤维化过程。免疫组化和原位杂交技术证实了纤维化皮损中上述因子的存在。硬皮病和瘢痕疙瘩成纤维细胞在体外也显示了对细胞因子的异常反应。损伤、炎症或自身免疫过程中某些细胞因子浓度增加可引起纤维化特有的多效性遗传程序的活化。成纤维细胞内细胞因子调节程序的内在改变也可能与纤维化有关。     

富含半胱氨酸的酸性分泌糖蛋白与皮肤纤维化疾病

富含半胱氨酸的酸性分泌糖蛋白是纤维化疾病进程中的一个关键因素.体内外实验表明,其能影响多种细胞的活动,富含半胱氨酸的酸性分泌糖蛋白及其相关的肽与细胞外基质结合,影响细胞外基质的表达,改变细胞形态变化、降低细胞的黏附性、影响细胞的迁移、调节生长因子诱导的细胞增殖及血管发生.这些功能同纤维化的发生、发展密切相关.鉴于富含半胱氨酸的酸性分泌糖蛋白在多种纤维化疾病中的重要作用,概述其与系统性硬化病、创伤愈合及病理性瘢痕之间的关系及作用机制.     

Localized scleroderma: clinical spectrum and therapeutic update

Scleroderma is a rare connective tissue disease that is manifested by cutaneous sclerosis and variable systemic involvement. Two categories of scleroderma are known: systemic sclerosis, characterized by cutaneous sclerosis and visceral involvement, and localized scleroderma or morphea which classically presents benign and self-limited evolution and is confined to the skin and/or underlying tissues. Localized scleroderma is a rare disease of unknown etiology. Recent studies show that the localized form may affect internal organs and have variable morbidity. Treatment should be started very early, before complications occur due to the high morbidity of localized scleroderma. In this review, we report the most important aspects and particularities in the treatment of patients diagnosed with localized scleroderma.     

Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma

Abstract:  Localized scleroderma is a connective tissue disorder that is limited to the skin and subcutaneous tissue. Macrophages have been reported to be particularly activated in patients with skin disease including systemic sclerosis and are potentially important sources for fibrosis-inducing cytokines, such as transforming growth factor β. To clarify the features of immunohistochemical characterization of the immune cell infiltrates in localized scleroderma focusing on macrophages, skin biopsy specimens were analysed by immunohistochemistry. The number of cells stained with monoclonal antibodies, CD68, CD163 and CD204, was calculated. An evident macrophage infiltrate and increased number of alternatively activated macrophages (M2 macrophages) in their fibrotic areas were observed along with their severity of inflammation. This study revealed that alternatively activated macrophages (M2 macrophages) may be a potential source of fibrosis-inducing cytokines in localized scleroderma, and may play a crucial role in the pathogenesis of localized scleroderma.     

Expression of CD1a and CD86 on scleroderma Langerhans cells

Scleroderma is a chronic autoimmune connective tissue disorder of unknown etiology that affects the microvasculature and loose connective tissue. Langerhans cells play an important role in the immune system of the skin. By immunohistochemistry we investigated the phenotypical characteristics of epidermal and dermal Langerhans cells and their spatial relationship with infiltrating lymphocytes in systemic scleroderma (SSc) and localized scleroderma. Skin samples were obtained from patients by 6 mm punch biopsy. Samples were stained with antibodies against CD1a and CD86. The number of cells stained with both antibodies in the dermal and epidermal infiltration was calculated. In contrast to normal skin, both types of scleroderma skin showed a marked increase in CD1a+ dermal Langerhans cells, whereas the number of CD1a+ cells in localized scleroderma was much higher than that in SSc (p < 0.05) either in the dermis or in the epidermis. The expression of CD86 was increased in the dermis of localized scleroderma compared with that in SSc or normal skin (p < 0.05). This study revealed that Langerhans cells may play an important role in the pathogenesis of scleroderma, especially in localized scleroderma. CD86 is predominantly expressed on dermal Langerhans cells in the lesional skin of localized scleroderma. Therefore, it might play an important role in the pathogenesis of localized scleroderma.     

Immunohistochemical characterization of the cellular infiltrate in localized scleroderma

Background Localized scleroderma is a connective tissue disorder with hardening of the skin and fibrosis of the affected tissue as the most prominent features. The etiology of localized scleroderma is still unknown, but immunologic factors may play an important role in the pathogenesis. This study was performed to determine the immunohistochemical features of the cellular infiltrate in localized scleroderma. Methods Skin samples were obtained from six patients by 6‐mm punch biopsy. The samples were stained with monoclonal antibodies against CD1a, CD3, CD4, CD8, CD20, CD25, CD30, and CD57. The number of cells stained with each monoclonal antibody was calculated. Results There were more CD1a+, CD3+, CD4+, CD8+, CD20+, CD25+, and CD57+ cells in the dermal infiltrate in localized scleroderma relative to those in normal controls. The numbers of CD1a+, CD3+, CD4+, CD8+, and CD57+ cells in localized scleroderma were significantly greater than those in normal skin (P < 0.05). The number of CD30+ cells in localized scleroderma was almost the same as that in normal skin. Conclusions This study reveals that T lymphocytes, Langerhans cells, and natural killer cells may play important roles in the pathogenesis of localized scleroderma.     

Chronic venous insufficiency – a potential trigger for localized scleroderma

Localized scleroderma is a cutaneous disease that is characterized by an initial inflammatory response, followed by sclerosis of the skin. The cause of localized scleroderma has not yet been determined. Seifarth et al. reported two cases of localized scleroderma at sites of chronic venous insufficiency. We document here three more patients in whom localized scleroderma was located at insufficient veins. Treatment of underlying chronic venous insufficiency (CVI) leads to a substantial clinical improvement of scleroderma at the site of insufficient veins, but not elsewhere. Experimental data support the concept of chronic venous insufficiency creating a microenvironment, which may lead to localized scleroderma. Local hypoxaemia, which is present in CVI, induces the release of endothelium-derived cytokines, such as IL-1. Subsequently, expression of endothelial adhesion molecules and consequently leucocyte extravasation are induced. Infiltrating leucocytes secrete a number of inflammatory mediators, including transforming growth factor beta, which is a potent stimulus for collagen synthesis. Therefore, it may well be that CVI is a potential trigger factor for localized scleroderma. In addition, localized scleroderma may only develop if a certain amount of trigger factors are present - and resolves if one or more of the contributing factors (i.e. CVI) can be treated.     

Lokalisierte Sklerodermie (Morphea) im Kindesalter

Localized scleroderma or morphea is a sclerosing connective tissue disease of the skin, which may affect underlying tissues such as subcutis, muscle and bone. Many patients show extracutaneous symptoms and antinuclear antibodies, however, secondary transformation into systemic sclerosis does not occur. Localized scleroderma usually begins in childhood with a wide variation in its clinical spectrum. The linear variant is the most common subtype in children, associated with a progressive course and increased risk of complications. The disease may progress over years and result in severe functional and cosmetic disability. The etiology of localized scleroderma remains unknown. A genetic background is suspected, while triggers such as trauma, vaccinations and infections may lead to secondary immunologic phenomena. Localized scleroderma often remains unrecognized for a long time, resulting in substantial delay in treatment. The combination of systemic corticosteroids and methotrexate has been established as first-line therapy for progressive (usually linear) disease, whereas phototherapy (UVA-1 or UVB-narrow band) is suitable for adolescents with superficial circumscribed subtypes.     

Long‐standing morphea and the risk of squamous cell carcinoma of the skin

Scleroderma is a heterogeneous group of fibrosing connective tissue disorders of unknown etiology. Morphea is a localized form of scleroderma that occasionally leads to chronic erosions and ulcerations of the skin. Fibrosis, inflammation and chronic ulcerations may eventually promote skin neoplasms; morphea is therefore a rare but established risk factor for cutaneous squamous cell carcinoma (cSCC). We present a review of 16 scleroderma patients: 15 case reports from the literature (identified by a PubMed search) and one case from our clinic of a patient who had developed cSCC, and we discuss potential underlying mechanisms. Statistical analysis revealed that the lower extremities were the body site most commonly affected by cSCC in these scleroderma patients. The mean time interval between the onset of scleroderma and the development of cSCC was ten to twenty years. In patients with morphea, we recommend checking for skin tumors during follow‐up examinations as well as a careful risk‐benefit analysis when considering the application of immunosuppressants or phototherapy in view of their potential carcinogenic side effects.     

Insights into the molecular mechanism of chronic fibrosis: the role of connective tissue growth factor in scleroderma

Connective tissue growth factor (CCN2), a member of the CCN family of proteins, is a cysteine-rich matricellular protein. Connective tissue growth factor is not normally expressed in dermal fibroblasts unless induced. The most potent inducer of connective tissue growth factor thus far identified is transforming growth factor beta. Connective tissue growth factor, however, is constitutively overexpressed by fibroblasts present in skin fibrotic lesions, including scleroderma. The overexpression of connective tissue growth factor present in fibrotic lesions contributes to the phenotype of scleroderma in that connective tissue growth factor promotes matrix deposition, and fibroblast adhesion and proliferation. In animal models, whereas either transforming growth factor beta or connective tissue growth factor alone produce only a transient fibrotic response, connective tissue growth factor and transforming growth factor beta act together to promote sustained fibrosis. Thus the constitutive overexpression of connective tissue growth factor by fibroblasts present in fibrotic lesions would be expected to contribute directly to chronic, persistent fibrosis. This review discusses recent information regarding insights into connective tissue growth factor biology and, using scleroderma as a model system, the part connective tissue growth factor might play in fibrotic disease.     

D-penicillamine in the treatment of localized scleroderma

Localized scleroderma has no recognized internal organ involvement but may be disfiguring and disabling when the cutaneous lesions are extensive or affect children. There is no accepted or proven treatment for localized scleroderma. Case reports of 11 patients with severe, extensive localized scleroderma who were treated with D-penicillamine are summarized in this article. This drug was judged to have a favorable effect on the disease course in 7 (64%) of 11 patients. Improvement began within 3 to 6 months and consisted of cessation of active cutaneous lesions in all 7 patients, skin softening in 5, and more normal growth of the affected limb in 2 of 3 children. Joint stiffness and contractures also improved. The dose of D-penicillamine associated with a favorable response was as low as 2 to 5 mg/kg per day given over a period ranging from 15 to 53 months. D-Penicillamine caused nephrotic syndrome in 1 patient and milder reversible proteinuria in 3 other patients; none developed renal insufficiency. These data suggest that D-penicillamine may be effective in severe cases of localized scleroderma.     

结缔组织生长因子与皮肤纤维化疾病

结缔组织生长因子可能是决定纤维化进程的一个决定性因素，它具有促进细胞增殖和细胞外基质的合成与聚集、介导细胞黏附、刺激细胞迁移等作用。在纤维化组织中高表达。与硬皮病、病理性瘢痕等皮肤纤维化疾病的发生发展有着密切的关系。以结缔组织生长因子作为特异性靶位将为纤维化疾病的治疗开辟一个新的领域。