闭合蛋白表达异常与相关皮肤病

皮肤屏障由角质层、细胞间质和紧密连接组成.闭合蛋白是构成紧密连接的主要蛋白之一,存在于哺乳动物的皮肤、脑、神经系统和内脏组织中,在生理状态下影响紧密连接的整体性及其功能,是构成皮肤栅栏和屏障的主要功能蛋白之一.在人类组织中已发现27种闭合蛋白亚型,在上皮细胞间形成对电解质及溶质分子的屏障结构.研究表明,皮肤屏障功能受损是多种皮肤病如银屑病、特应性皮炎、家族性良性天疱疮、光线性角化病等重要的发病因素,这与闭合蛋白功能和结构的异常密切相关.闭合蛋白家族中不同成员在不同皮肤病中的表达各异.     

中间丝相关基因突变与皮肤病关联性的研究进展

中间丝相关蛋白是皮肤屏障中的一种重要的结构蛋白,对外界各种有害物质的入侵起到防御作用。中间丝相关蛋白相关基因突变或先天性缺陷,将导致这些蛋白质的异常表达,从而导致一系列以皮肤屏障功能损伤为特征的皮肤病发生。研究发现,中间丝相关蛋白基因突变与特应性皮炎以及寻常性鱼鳞病发病有明显的相关性;中间丝相关蛋白基因无义突变可能会降低镍接触性皮炎的发病年龄和增加对镍的敏感性;中间丝相关蛋白基因突变可能与斑秃、先天性厚甲综合征有关。总之,中间丝相关蛋白基因突变与多种皮肤疾病的发生有关联性,但目前中间丝相关蛋白基因突变是否为某一皮肤病的特征性致病因子仍需进一步研究。     

皮肤屏障功能解析

本文从皮肤的基本结构和生化组成入手,对表皮角蛋白分化、中间丝相关蛋白表达、角质层细胞间脂质以及皮肤水脂膜等不同层次上的皮肤物理性屏障功能进行了逐层分析,同时密切结合临床相关皮肤疾病的病因病理,对皮肤屏障结构的异常变化进行了讨论。皮肤屏障功能是皮肤科最基本的问题之一。深入研究皮肤的屏障功能,从皮肤屏障功能的视角审视众多皮肤病,可能会有新的启发和认识。     

皮肤屏障功能异常与银屑病

人的皮肤具有屏障功能,它在保护皮肤抵御外界刺激及保持皮肤微环境的稳态中起到重要作用。银屑病是一种通过表皮角化细胞和免疫细胞的相互作用引起的慢性炎症性皮肤病,目前其发病机理尚不明确。最近的研究揭示了表皮屏障相关基因的缺陷与银屑病的风险相关。越来越多的研究表明,皮肤屏障功能的异常,与银屑病的发病有着密切的关系,可能是银屑病发病的主要诱因之一。     

外用糖皮质激素对皮肤屏障系统的影响

短期局部外用糖皮质激素会明显降低皮肤屏障功能的恢复速度,长期使用糖皮质激素则会引起屏障结构的改变。外用糖皮质激素对皮肤屏障的破坏机制众多,其中包括抑制角质形成细胞增殖,影响角蛋白、中间丝聚合蛋白的分化、影响角化桥粒、角质形成细胞间质的形成等。因此,在糖皮质激素依赖性皮炎的治疗及使用糖皮质激素进行疾病的治疗中应适当使用皮肤屏障保护产品。     

肥胖对皮肤生理功能的影响及其伴发和加重的皮肤病

肥胖已被认为是主要的公共健康问题之一[1].肥胖可增加冠心病、高血压、高脂血症、骨关节炎、糖尿病的发病风险,与失眠、内分泌失调、直肠癌、胆囊疾病、骨骼肌疾病、重症胰腺炎、营养不良、尿失禁、特发性颅内高压等直接相关,还与焦虑、抑郁、社交障碍等间接相关.然而,肥胖对皮肤的影响则很少有人关注.肥胖可使皮肤屏障功能、皮脂腺和汗腺功能、胶原结构和功能、创伤愈合、皮肤微循环以及皮下脂肪等皮肤生理功能发生改变.此外,肥胖可伴发或加重多种皮肤病,如黑棘皮病、毛周角化病、软纤维瘤、多毛症、萎缩纹、痛性肥胖症、皮肤淋巴水肿、掌跖角化症、蜂窝织炎、化脓性汗腺炎、痛风、银屑病等.我们综述了其临床特征以及与肥胖的关系,以阐明肥胖对某些皮肤病的重要影响.     

皮肤屏障受损及其相关皮肤病的研究进展

皮肤屏障结构与功能受损与多种皮肤疾病关系密切,维持皮肤屏障结构和功能稳定对防止病原体侵入、减轻皮肤炎性反应等有重要意义。敏感肌是皮肤的一种高度敏感状态,其病因复杂,目前多认为皮肤屏障功能受损是敏感肌发生的最主要因素。本文围绕皮肤屏障结构、功能与敏感肌及其他相关皮肤病进行讨论,并在此基础上总结了多重皮肤屏障修复对缓解敏感肌及其他皮肤屏障受损相关疾病的必要性。     

痤疮与皮肤屏障

痤疮是一种好发于青少年常见的毛囊皮脂腺的慢性炎症性皮肤病,可导致炎症后色素沉着和永久性瘢痕。痤疮的发生发展与皮肤屏障功能有着密切的关系,痤疮发病机制中皮脂分泌增多、毛囊上皮角化过度、致病性痤疮丙酸杆菌定植、炎症反应等因素均会引起皮肤屏障功能损伤,而皮肤屏障功能的损伤加剧了痤疮病情。因此,在治疗痤疮的同时,修复皮肤屏障功能是痤疮防治的重要环节。     

特应性皮炎相关细胞因子对皮肤屏障的影响

【摘要】 皮肤是人体最大的器官,是一个重要的屏障。特应性皮炎患者存在皮肤屏障功能异常,同时其细胞因子的组成与健康人不同。在特应性皮炎患者皮肤中发现的许多细胞因子能够影响角质形成细胞的分化和角化过程。本文综述了特应性皮炎相关细胞因子的最新进展及其对皮肤屏障功能的影响,这些结果有利于了解特应性皮炎的发病机制,并可能为特应性皮炎的治疗提供新的方向。     

中间丝蛋白与特应性皮炎皮肤屏障功能

特应性皮炎的病因复杂,发病机制尚未明确,可能是遗传、环境、皮肤屏障功能缺陷及免疫相互作用的结果.中间丝蛋白基因是表皮分化复合物基因簇的成员之一,与细胞膜形成及表皮终末分化密切相关.中间丝蛋白基因突变是特应性皮炎发病的重要易患因素之一,中间丝蛋白的减少和缺失,可能是引起特应性皮炎等十燥性皮肤病的主要原因.     

The skin: an indispensable barrier

Abstract: The skin forms an effective barrier between the organism and the environment preventing invasion of pathogens and fending off chemical and physical assaults, as well as the unregulated loss of water and solutes. In this review we provide an overview of several components of the physical barrier, explaining how barrier function is regulated and altered in dermatoses. The physical barrier is mainly localized in the stratum corneum (SC) and consists of protein‐enriched cells (corneocytes with cornified envelope and cytoskeletal elements, as well as corneodesmosomes) and lipid‐enriched intercellular domains. The nucleated epidermis also contributes to the barrier through tight, gap and adherens junctions, as well as through desmosomes and cytoskeletal elements. During epidermal differentiation lipids are synthesized in the keratinocytes and extruded into the extracellular domains, where they form extracellular lipid‐enriched layers. The cornified cell envelope, a tough protein/lipid polymer structure, resides below the cytoplasmic membrane on the exterior of the corneocytes. Ceramides A and B are covalently bound to cornified envelope proteins and form the backbone for the subsequent addition of free ceramides, free fatty acids and cholesterol in the SC. Filaggrin is cross‐linked to the cornified envelope and aggregates keratin filaments into macrofibrils. Formation and maintenance of barrier function is influenced by cytokines, 3′,5′‐cyclic adenosine monophosphate and calcium. Changes in epidermal differentiation and lipid composition lead to a disturbed skin barrier, which allows the entry of environmental allergens, immunological reaction and inflammation in atopic dermatitis. A disturbed skin barrier is important for the pathogenesis of contact dermatitis, ichthyosis, psoriasis and atopic dermatitis.     

A topical Chinese herbal mixture improves epidermal permeability barrier function in normal murine skin

Chinese herbal medicine (CHM) has been shown to have beneficial effects for both skin disorders with barrier abnormality and as skin care ingredients. Yet, how CHM exerts their benefits is unclear. As most, if not all, inflammatory dermatoses are accompanied by abnormal permeability barrier function, we assessed the effects of topical CHM extracts on epidermal permeability barrier function and their potential mechanisms. Topical CHM accelerated barrier recovery following acute barrier disruption. Epidermal lipid content and mRNA expression of fatty acid and ceramide synthetic enzymes increased following topical CHM treatment in addition to mRNA levels for the epidermal glucosylceramide transport protein, ATP-binding cassette A12. Likewise, CHM extract increased mRNA expression of antimicrobial peptides both in vivo and in vitro. These results demonstrate that the topical CHM extract enhances epidermal permeability barrier function, suggesting that topical CHM could provide an alternative regimen for the prevention/treatment of inflammatory dermatoses accompanied by barrier abnormalities.     

The role of ceramides in skin homeostasis and inflammatory skin diseases

Ceramides, members of sphingolipid family, are not only the building blocks of epidermal barrier structure, but also bioactive metabolites involved in epidermal self-renewal and immune regulation. Hence, abnormal ceramide expression profile is recognized to defect extracellular lipid organization, disturb epidermal self-renewal, exacerbate skin immune response and actively participate in progression of several inflammatory dermatoses, exemplifying by psoriasis and atopic dermatitis. Here, we discuss recent advances in understanding skin ceramides and their regulatory roles in skin homeostasis and pathogenic roles of altered ceramide metabolism in inflammatory skin diseases. These insights provide new opportunities for therapeutic intervention in inflammatory dermatoses.     

Omega-hydroxyceramides are required for corneocyte lipid envelope (CLE) formation and normal epidermal permeability barrier function

Omega-hydroxyceramides (omega-OHCer) are the predominant lipid species of the corneocyte lipid envelope in the epidermis. Moreover, their omega-esterified-derivatives (acylCer) are major components of the stratum corneum extracellular lamellae, which regulate cutaneous permeability barrier function. Because epidermal omega-OHCer appear to be generated by a cytochrome P450-dependent process, we determined the effects of a mechanism-based inhibitor of omega-hydroxylation, aminobenzotriazole (ABT), on epidermal omega-OH Cer formation and barrier function. We first ascertained that ABT, but not hydroxybenzotriazole (OHBT), a chemical relative with no P450 inhibitory activity, inhibited the incorporation of [14C]-acetate into the omega-OH-containing Cer species in cultured human keratinocytes (68.1% +/- 6.9% inhibition versus vehicle-treated controls; p < 0.001), without altering the synthesis of other Cer and fatty acid species. In addition, ABT significantly inhibited the omega-hydroxylation of very long-chain fatty acids in cultured human keratinocytes. Topical application of ABT, but not OHBT, when applied to the skin of hairless mice following acute barrier disruption by tape-stripping, resulted in a significant delay in barrier recovery (e.g., 38.3% delay at 6 h versus vehicle-treated animals), assessed as increased transepidermal water loss. The ABT-induced barrier abnormality was associated with: (i) a significant decrease in the quantities of omega-OHCer in both the unbound and the covalently bound Cer pools; (ii) marked alterations of lamellar body structure and contents; and (iii) abnormal stratum corneum extracellular lamellar membrane structures, with no signs of cellular toxicity. Furthermore, pyridine-extraction of ABT- versus vehicle-treated skin, which removes all of the extracellular lamellae, leaving the covalently attached lipids, showed numerous foci with absent corneocyte lipid envelope in ABT- versus vehicle-treated stratum corneum. These results provide the first direct evidence for the importance of omega-OHCer for epidermal permeability function, and suggest further that acylCer and/or corneocyte lipid envelope are required elements in permeability barrier homeostasis.     

Bioactive: A new era of bioactive ingredients in topical formulations for inflammatory dermatoses

Moisturization is the pillar of daily skin care and has significant benefit in improving hydration, strengthening the skin barrier, and ameliorating inflammatory dermatoses. Bioactive ingredients such as endocannabinoids, bioactive lipids, growth factors, microbiome modulators, and antioxidant enzymes are increasingly being incorporated into moisturizer formulations. These novel ingredients have been shown to improve skin barrier function, upregulate barrier lipid synthesis, decrease itch and inflammation, and have antioxidative properties. In this article, we highlight evidence supporting their mechanisms of action and efficacy in atopic dermatitis, uremic pruritus, asteatotic eczema, acne vulgaris, and vitiligo.     

Ceramides and skin function

Ceramides are the major lipid constituent of lamellar sheets present in the intercellular spaces of the stratum corneum. These lamellar sheets are thought to provide the barrier property of the epidermis. It is generally accepted that the intercellular lipid domain is composed of approximately equimolar concentrations of free fatty acids, cholesterol, and ceramides. Ceramides are a structurally heterogeneous and complex group of sphingolipids containing derivatives of sphingosine bases in amide linkage with a variety of fatty acids. Differences in chain length, type and extent of hydroxylation, saturation etc. are responsible for the heterogeneity of the epidermal sphingolipids. It is well known that ceramides play an essential role in structuring and maintaining the water permeability barrier function of the skin. In conjunction with the other stratum corneum lipids, they form ordered structures. An essential factor is the physical state of the lipid chains in the nonpolar regions of the bilayers. The stratum corneum intercellular lipid lamellae, the aliphatic chains in the ceramides and the fatty acids are mostly straight long-chain saturated compounds with a high melting point and a small polar head group. This means that at physiological temperatures, the lipid chains are mostly in a solid crystalline or gel state, which exhibits low lateral diffusional properties and is less permeable than the state of liquid crystalline membranes, which are present at higher temperatures. The link between skin disorders and changes in barrier lipid composition, especially in ceramides, is difficult to prove because of the many variables involved. However, most skin disorders that have a diminished barrier function present a decrease in total ceramide content with some differences in the ceramide pattern. Formulations containing lipids identical to those in skin and, in particular, some ceramide supplementation could improve disturbed skin conditions. Incomplete lipid mixtures yield abnormal lamellar body contents, and disorder intercellular lamellae, whereas complete lipid mixtures result in normal lamellar bodies and intercellular bilayers. The utilization of physiological lipids according to these parameters have potential as new forms of topical therapy for dermatoses. An alternative strategy to improving barrier function by topical application of the various mature lipid species is to enhance the natural lipid-synthetic capability of the epidermis through the topical delivery of lipid precursors.     

The effect of UV-A and UV-B irradiation on the skin barrier. Skin physiologic, electron microscopy and lipid biochemistry studies]

In order to gain insight into the effects of UV-irradiation on the skin barrier, functional (skin reactivity), electron microscopic and lipid-biochemical studies were performed. In three different irritation models, both UV-A-irradiated and UV-B-irradiated areas proved to be more resistant to damage than normal skin, providing evidence for improvement of barrier function after UV irradiation. Electron microscopic evaluation showed that UV-B induced a significant increase in horny cell layers, whereas after UV-A no change was detected. However, both UV-B and UV-A exposure resulted in an increase in the amount of all stratum corneum lipids. This was also observed in all major ceramide subfractions, which are believed to be the essential lipid constituents for the epidermal barrier function. These findings may explain the known beneficial effects of phototherapy in dermatoses with impaired barrier function, i.e., atopic dermatitis.     

Localization of sphingomyelin during the development of dorsal and tail epidermis of mice

BACKGROUND: The water permeability barrier of the stratum corneum seems to be regulated primarily by lamellar bodies situated between the corneocytes; the lamellar bodies originate largely from polar lipid precursors, mainly sphingomyelin (SM), provided by the cells of the stratum granulosum via exocytosis of their lamellar body content. OBJECTIVES: The aim of our study was to evaluate the cellular distribution of SM during development of the epidermis. Methods In this study, we investigated the expression and localization of SM in both adult and fetal mouse skin by a cytochemical detection method, immunofluorescence microscopy and immunoelectron microscopy, using anti-SM antibody, a specific binding protein to SM (lysenin), and Nile red stain. In addition, we measured transepidermal water loss to estimate the barrier function of the fetal skin. RESULTS: We observed that SM was widely distributed from the basal layer to the granular layer in the adult mouse epidermis. An intense cytochemical reaction for SM was observed on embryonic day E14.5 of gestation just before the differentiation of the granular and squamous cells from the intermediate cells. The immunofluorescence indicating SM was detected in two regions, i.e. the most superficial zone of the granular layer and the upper spinous layer after the cell differentiation at the late gestational age. This distribution was not detected by conventional lipid staining, such as with Nile red stain. Immunoelectron microscopy revealed that SM was mainly localized in the intercellular spaces of the adult mouse epidermis and in the intracellular vesicles without a complete lamellar structure in the cytoplasm of epidermal cells of E14.5 fetuses. It is well known that the formation of the structurally mature cornified cell envelope occurs at E15.5 of development. The skin of fetuses at E16.5 showed a definite barrier function. CONCLUSIONS: These findings suggest that SM dynamics is related to the formation of the lipid envelope, cell differentiation, and epidermal barrier function during development.     

Barrier function of the skin: "la raison d'être" of the epidermis

The primary function of the epidermis is to produce the protective, semi-permeable stratum corneum that permits terrestrial life. The barrier function of the stratum corneum is provided by patterned lipid lamellae localized to the extracellular spaces between corneocytes. Anucleate corneocytes contain keratin filaments bound to a peripheral cornified envelope composed of cross-linked proteins. The many layers of these specialized cells in the stratum corneum provide a tough and resilient framework for the intercellular lipid lamellae. The lamellae are derived from disk-like lipid membranes extruded from lamellar granules into the intercellular spaces of the upper granular layer. Lysosomal and other enzymes present in the extracellular compartment are responsible for the lipid remodeling required to generate the barrier lamellae as well as for the reactions that result in desquamation. Lamellar granules likely originate from the Golgi apparatus and are currently thought to be elements of the tubulo-vesicular trans-Golgi network. The regulation of barrier lipid synthesis has been studied in a variety of models, with induction of several enzymes demonstrated during fetal development and keratinocyte differentiation, but an understanding of this process at the molecular genetic level awaits further study. Certain genetic defects in lipid metabolism or in the protein components of the stratum corneum produce scaly or ichthyotic skin with abnormal barrier lipid structure and function. The inflammatory skin diseases psoriasis and atopic dermatitis also show decreased barrier function, but the underlying mechanisms remain under investigation. Topically applied "moisturizers" work by acting as humectants or by providing an artificial barrier to trans-epidermal water loss; current work has focused on developing a more physiologic mix of lipids for topical application to skin. Recent studies in genetically engineered mice have suggested an unexpected role for tight junctions in epidermal barrier function and further developments in this area are expected. Ultimately, more sophisticated understanding of epidermal barrier function will lead to more rational therapy of a host of skin conditions in which the barrier is impaired.     

Advancements in the maintenance of skin barrier/skin lipid composition and the involvement of metabolic enzymes

The human skin barrier has an important role in protection and defense, reflected not only in the ability to resist entry of harmful substances into the human body, but also in the ability to prevent loss of water and nutrients. Once the skin barrier is damaged, the skin may become dry, scaly, and wrinkled, and a series of skin problems may occur. In this article, we review the composition of lipids, such as ceramides, cholesterol, and free fatty acids, in the skin and examine the expression of enzymes related to lipid metabolism, such as kallikreins, elongase of elongation of very long‐chain fatty acids, hydrolases, and lipid synthases. Additionally, we discuss the involvement of these proteins in skin barrier function and structure. The information presented in this review is expected to provide a theoretical basis for the development of skin care products facilitating the maintenance and repair of skin barrier function.