表皮通透屏障功能与表皮CD44表达关系的研究

目的:研究表皮通透屏障功能破坏后表皮CD44的表达.方法:外用胶带破坏裸鼠躯干部表皮通透屏障功能,分别于30min、1 h、3 h、6 h、24 h和48 h后取皮肤标本,用免疫组化的方法观察CD44在表皮的表达.结果:在表皮通透屏障功能破坏后30 min,表皮CD44的表达明显上调;1 h和3 h后,恢复至正常水平;6 h后,表皮CD44的表达又明显增强,并持续到48 h;人为地纠正屏障功能(封包)对表皮CD44的表达没有明显影响.结论:表皮通透屏障功能破坏后,表皮CD44的表达增强,其表达的改变与屏障功能本身无显著相关性.     

皮肤科学基础

蒿甲醚对紫外线照射后HaCaT细胞表达Fas和Bcl-2的影响;表皮通透屏障功能与表皮CD44表达关系的研究;诱导型一氧化氦合酶在人皮肤自然衰老过程中的表达和意义;两种人乳头瘤病毒分型检测方法的比较;皮肤组织的热力学行为表征：Ⅱ．黏弹性行为;糖皮质激素外用制剂与其他外用制剂混合及稀释使用的探讨（综述）;     

皮肤表面酸碱度稳态动力学的研究

目的:探索皮肤保持其表面pH稳定状态的动力学.方法:利用丙酮和胶带急性破坏表皮通透屏障功能、中波紫外线(UVB)照射及局部外用碱性物质的方法提高皮肤表而pH值.然后,在不同的时间观察皮肤表而pH的改变,依此判断皮肤表面pH保持稳定状态的动力学.结果:在丙酮事模型中,表皮通透屏障功能破坏48 h后,皮肤表面的pH恢复正常;而在胶带模型中,表皮通透屏障功能破坏48 h后,皮肤表面的pH值仍明显地高于基础值(P<0.01);在紫外线模型中,UVB照射6 d后,皮肤表面的pH才恢复正常;局部外用碱性物质6 h后,皮肤表面pH恢复正常.结论:皮肤维持其表面pH稳定状态的动力学因诱导pH紊乱的因素不同而不同.     

银屑病表皮通透屏障功能的改变及其临床意义

表皮通透屏障功能的改变与多种皮肤病的发生和发展有关.银屑病是病因不明、发病机制不清、复发率高的常见病.银屑病患者皮损的主要病理改变为皮肤炎症细胞浸润、表皮增生过度、角化不全以及表皮分化蛋白表达降低.表皮通透屏障功能降低是其重要的皮肤生理特性改变之一.尽管表皮通透屏障功能降低与银屑病的因果关系尚不清楚,但大多学者赞同两者间是相互影响的.了解银屑病表皮通透屏障功能的改变及其机制或许对其病情评估和防治有一定的参考价值.     

评估表皮通透屏障功能的方法及其应用

表皮通透屏障功能是指表皮防止物质通过表皮进出机体的功能.该功能对于表皮的增生分化、炎症的形成与发展以及抗微生物感染等方面都具有重要作用.而表皮通透屏障功能受体内外多种生物、物理因素的影响.因此,调节表皮通透屏障功能是皮肤保健和防治某些皮肤病的重要手段;评估表皮通透屏障功能是了解皮肤生物功能以及判断皮肤保健、治疗效果的方法.评估表皮通透屏障功能的方法很多.除测量透皮失水率外,超微示踪、透皮微昔分析、同位素及荧光标记定位和定量等都是评估表皮通透屏障功能的有效方法.了解这些方法的特点对于选择恰当的手段和有效地评估表皮通透屏障功能具有重要的指导意义.     

老年人表皮通透屏障功能的改变及其临床意义

表皮通透屏障是机体抵御外界有害物质侵入和阻止体内物质丢失的一道重要屏障。随着机体衰老,表皮角质形成细胞增生分化能力降低、脂质合成减少,而表皮pH升高,最终导致表皮通透屏障功能恢复速度减慢。表皮通透屏障功能的降低,不仅加快皮肤和血液中炎症因子的增多,还会增大皮肤感染风险。皮肤炎症因子持续表达增高可引起慢性皮肤瘙痒等,同时可诱发和加重系统性炎症,参与多种系统性疾病的发生与发展。因此,改善老年表皮通透屏障功能将可能成为预防和治疗某些老年疾病的有效方法之一。     

改善表皮通透屏障功能对特应性皮炎的防治作用

表皮通透屏障是皮肤的防御功能之一,它不仅影响物质透过皮肤进出机体以及微生物的侵入,对皮肤的其他生物功能也具有重要的调节作用［１］。表皮通透屏障功能降低是一些皮肤病（包括特应性皮炎和银屑病）发病的主要因素之一［2］。改善表皮通透屏障功能有助于防治这些皮肤病,已成为防治特应性皮炎的手段之一。由于改善表皮通透屏障功能的制剂或有效活性成分不同,其对皮肤功能的影响也不同。因此,在临床上选择改善表皮通透屏障功能的制剂时,应综合考虑皮肤的生物物理特性和不同制剂的特性,使其发挥最大的疗效。在此,仅综述几种主要改善表皮通透屏障功能的制剂对特应性皮炎的防治作用……     

透明质酸及其受体CD44在麻风患者愈后表皮中的表达

目的研究透明质酸及其受体CD44在麻风患者皮损愈后者表皮的表达是否发生改变。方法用免疫组化方法比较透明质酸及其受体CD44在不同类型麻风患者愈后及正常表皮中的表达。结果与正常表皮比较,透明质酸在LL、BL及BT型麻风患者皮损愈后表皮的表达明显增强;而在TT型表皮的表达没有明显的改变;在BB型基底层的表达也轻微减弱。CD44在BB,BT及TT类型麻风患者愈后表皮的表达均增强,尤其是TT型。而在LL型的表达则轻微减弱。CD44在BL型的表达没有明显改变。结论麻风患者愈后表皮透明质酸及CD44的表达均有改变。     

表皮通透的屏障功能及其调节

保护机体、防止过多的水分丢失是皮肤的主要功能之一,角质层角质形成细胞及其细胞间脂类的组分对此功能起决定作用。角质形成细胞间的复层板层膜是皮肤屏障功能的主要结构。表皮通透的屏障功能影响皮肤的水分丢失量,且对表皮及真皮的生物活性(如角质形成细胞的增生、皮肤的炎症等)均有调节作用。诸多因素如脂类、性别、年龄、酸碱度、离子及精神等均可以作用于表皮通透的屏障功能。因此,深入地了解表皮通透的屏障功能及其影响因素有助于皮肤病的防治。     

老年表皮功能与老年炎症

【摘要】 目前研究认为，老年病包括心血管疾病、2型糖尿病以及阿尔茨海默症等的发生与衰老相关的慢性炎症（“炎症性衰老”）有关，但是炎症的来源一直未知。有研究显示，老年表皮功能异常可能是老年炎症的根源。与年轻人相比，老年人表皮功能的变化包括角质层含水量降低、皮肤表面pH值升高以及表皮通透屏障功能恢复速度减慢，这些改变均能导致皮肤炎症。瘙痒症好发于老年人，瘙痒引起的搔抓可进一步破坏表皮通透屏障功能和诱发炎症。皮肤持续轻微的炎症有可能导致系统炎症。在老年小鼠和老年人的研究均证明，改善表皮功能可以降低循环血炎症细胞因子表达量，提示老年表皮功能异常可能是老年炎症的根源，改善表皮功能可能有助于预防和缓解老年病。     

The role of CD44 in cutaneous inflammation

Abstract:  CD44 is a transmembrane glycoprotein expressed in various tissues including the skin. Previous studies indicated that CD44 is required for epidermal permeability barrier homeostasis and keratinocyte differentiation. Yet, while some studies have demonstrated that CD44 is critical for the development of inflammation, others have shown that CD44 is not essential for the development of cutaneous inflammation. In this study, we evaluated the changes in epidermal CD44 expression in a variety of skin inflammatory models and determined whether CD44 is required for the development of cutaneous inflammation. Inflammatory responses were compared in CD44 KO versus wild-type mice in acute models of irritant and allergic contact dermatitis, as well as in a subacute allergic contact dermatitis induced by repeated hapten treatment. Inflammatory responses were assessed by measuring ear thickness and epidermal hyperplasia in haematoxylin & eosin-stained sections. Our results demonstrate that: (i) epidermal CD44 expression increases in both acute and subacute cutaneous inflammatory models; and (ii) acute disruption of the epidermal permeability barrier function increases epidermal CD44 expression. Whereas inflammatory responses did not differ between CD44 KO and wild-type mice in acute models of irritant and allergic contact dermatitis, both inflammatory responses and epidermal hyperplasia increased in CD44 KO mice following repeated hapten challenges. These results show first, that permeability barrier disruption and inflammation stimulate epidermal CD44 expression, and second, that CD44 modulates epidermal proliferation and inflammatory responses in a subacute murine allergic contact dermatitis model.     

Hyaluronan-CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis

In this study we investigated whether hyaluronan (HA)-CD44 interaction influences epidermal structure and function. Our data show that CD44 deficiency is accompanied by reduction in HA staining in CD44 knockout (k/o) mouse skin leading to a marked thinning of epidermis versus wild-type mouse skin. A significant delay in the early barrier recovery (following acute barrier disruption) occurs in CD44 k/o versus wild-type mouse skin. To assess the basis for these alterations in CD44 k/o mouse epidermis, we determined that differentiation markers are greatly reduced in the epidermis of CD44 k/o versus wild-type mice, while conversely HA binding to CD44 triggers differentiation in cultured human keratinocytes. CD44 downregulation (using CD44 small interfering RNAs) also inhibits HA-mediated keratinocyte differentiation. Slower barrier recovery in CD44 k/o mice could be further attributed to reduced lamellar body formation, loss of apical polarization of LB secretion, and downregulation of cholesterol synthesis. Accordingly, HA-CD44 binding stimulates both LB formation and secretion. Together, these observations demonstrate new roles for HA-CD44 interaction in regulating both epidermal differentiation and lipid synthesis/secretion, which in turn influence permeability barrier homeostasis. HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function.     

CD44 regulates tight-junction assembly and barrier function

Upon barrier disturbance, adult CD44 knockout (KO) mice show delayed recovery of epidermal barrier function. This correlates with the loss of apical polarization of lamellar body (LB) secretion. As tight junctions (TJs) are crucial for barrier function and regulate polarized targeting of vesicles, we hypothesized that CD44 regulates TJs and associated cell polarity complexes, which in turn contributes to altered skin barrier function in CD44 KO mice. We show a delay in embryonic barrier formation associated with a loss of apical LB localization in CD44 KO mice, which correlates with alterations in TJ proteins and Par3. Simultaneously, the activity of Rac1, a major regulator of TJ barrier function, was reduced. Importantly, normalization of barrier function at E18.5 coincided with the recovery of these proteins. Tape-stripping experiments revealed that the loss of CD44 also affected TJ proteins upon induced disturbance of the barrier in adult mice. In CD44 KO keratinocytes, cell polarization and TJ barrier function were impaired. An alteration of differentiation markers was also observed, but was less pronounced than alterations of TJ proteins. Taken together, the results reveal an important function for CD44 in the assembly and function of TJs, suggesting their involvement in the skin barrier phenotype of CD44 KO mice.     

Transient CD44 variant isoform expression and reduction in CD4(+)/CD25(+) regulatory T cells in C3H/HeJ mice with alopecia areata

Alopecia areata, an autoimmune disease affecting anagen stage hair follicles, can be induced by grafting spontaneous alopecia areata affected skin to normal-haired C3H/HeJ mice. As the onset of alopecia areata can be significantly retarded by anti-CD44 variant isoform 10 treatment, it was interesting to explore the underlying disease mechanism. Two weeks after transplanting alopecia areata affected skin, expression of CD44 variant isoforms 3, 6, 7, and 10 was strikingly upregulated as compared with sham-grafted mice. By 6 wk after grafting, CD44 variant isoform levels had returned to normal, whereas in draining lymph nodes, CD44 variant isoform expression was slightly decreased. Leukocytes in the skin of mice with chronic alopecia areata expressed a hematopoietic isoform of CD44 and CD44 variant isoform 6 at an elevated level, but CD44 variant isoform 3 expression was reduced. Cytokine expression in leukocytes of chronic alopecia areata affected skin was higher than in normal-haired controls. Cytokine expression also increased postsurgery in sham and alopecia areata grafted mice, but remained elevated only in mice receiving alopecia areata affected skin. Finally, from the skin of mice with chronic alopecia areata and of mice transplanted with alopecia areata affected skin, an increased number of CD4(+) and CD8(+) cells, but a strongly decreased number of CD4(+)/CD25(+) regulatory T cells was recovered. Thus, expression of CD44 variant isoforms is important for the migration of leukocytes during the initial period of alopecia areata. CD44, however, is apparently not involved in the maintenance of the disease state, which is characterized by high cytokine expression levels, an increased number of CD4(+) and CD8+ cells, but a low level of CD4(+)/CD25(+) suppressor cells.     

Mechanisms by which psychologic stress alters cutaneous permeability barrier homeostasis and stratum corneum integrity

Although many skin disorders, including psoriasis and atopic dermatitis, are adversely affected by psychologic stress (PS), the pathophysiologic link between PS and disease expression remains unclear. Recent studies demonstrated PS-induced alterations in permeability barrier homeostasis, mediated by increased endogenous glucocorticoids. Here, we assessed the mechanisms by which PS alters stratum corneum (SC) function. Insomniac psychologic stress (IPS) altered both barrier homeostasis and SC integrity. IPS decreased epidermal cell proliferation, impaired epidermal differentiation, and decreased the density and size of corneodesmosomes (CD), which was linked to degradation of CD proteins (e.g., desmoglein1). Barrier compromise was linked to decreased production and secretion of lamellar bodies (LB), which in turn could be attributed to a decrease in de novo synthesis of epidermal lipids. Topical physiologic lipids (equimolar cholesterol, ceramides, and free fatty acids) normalized both barrier homeostasis and SC integrity in IPS mice, further evidence that lipid deficiency accounted for these functional abnormalities. Thus, PS inhibition of epidermal lipid synthesis results in decreased LB formation and secretion, as well as decreased CD, compromising both permeability barrier homeostasis and SC integrity. These studies suggest that topical treatment with epidermal physiologic lipids could be beneficial in stress-induced, barrier-associated dermatoses, such as psoriasis and atopic dermatitis.     

Topical hyaluronidase decreases hyaluronic acid and CD44 in human skin and in reconstituted human epidermis: evidence that hyaluronidase can permeate the stratum corneum

Hyaluronic acid (HA), a high molecular weight glycosaminoglycan of the extracellular matrix involved in growth, inflammation and wound healing, also contributes to the hydration and plastic properties of skin. Several drug and cosmetic formulations contain HA. We have initiated investigations that explore whether it is possible, by topical application, to modulate endogenous HA levels in skin. We developed a model epidermal culture system that exhibited a differentiated stratum corneum, and expressed HA and the HA receptor CD44, in a pattern similar to that observed in intact skin. Such in vitro skin equivalents are useful models for investigating the effect of topical drugs. HA and bacterial hyaluronidase were applied to the in vitro skin equivalent and to human skin. Their effects on endogenous HA and CD44 expression were examined using histochemical analysis. Topical HA treatment had no significant effect on HA or CD44 expression in either system. However, hyaluronidase decreased HA and CD44 expression in a dose-dependent manner in both the epidermal culture system and in skin. Apparently, HA is not able to permeate the epidermal culture system or human skin to a significant degree, but bacterial hyaluronidase does permeate both human skin and the culture system, depleting HA and decreasing CD44 expression. These effects were more prominent in the dermal than in the epidermal layers, suggesting that marked differences in HA metabolism exist in these two skin compartments. The ability of hyaluronidase to permeate the stratum corneum suggests that topical application may, additionally, be useful as a clinical modality.     

Psychological stress perturbs epidermal permeability barrier homeostasis: implications for the pathogenesis of stress-associated skin disorders

BACKGROUND: A large number of skin diseases, including atopic dermatitis and psoriasis, appear to be precipitated or exacerbated by psychological stress. Nevertheless, the specific pathogenic role of psychological stress remains unknown. In 3 different murine models of psychological stress, it was recently shown that psychological stress negatively impacts cutaneous permeability barrier function and that coadministration of tranquilizers blocks this stress-induced deterioration in barrier function. OBJECTIVES AND METHODS: The relationship between psychological stress and epidermal permeability barrier function was investigated in 27 medical, dental, and pharmacy students without coexistent skin disease. Their psychological state was assessed with 2 well-validated measures: the Perceived Stress Scale and the Profile of Mood States. Barrier function was assessed simultaneously with the stress measures at periods of presumed higher stress (during final examinations) and at 2 assumed, lower stress occasions (after return from winter vacation [approximately 4 weeks before final examinations] and during spring vacation [approximately 4 weeks after final examinations]). RESULTS: The subjects as a group demonstrated a decline in permeability barrier recovery kinetics after barrier disruption by cellophane tape stripping, in parallel with an increase in perceived psychological stress during the higher vs the initial lower stress occasions. During the follow-up, presumed lower stress period, the subjects again displayed lower perceived psychological stress scores and improved permeability barrier recovery kinetics, comparable to those during the initial lower stress period. Moreover, the greatest deterioration in barrier function occurred in those subjects who demonstrated the largest increases in perceived psychological stress. CONCLUSION: These studies provide the first link between psychological status and cutaneous function in humans and suggest a new pathophysiological paradigm, ie, stress-induced derangements in epidermal function as precipitators of inflammatory dermatoses.     

Odorant inhalation affects skin barrier homeostasis in mice and humans

Previous studies have suggested that psychological stress delays cutaneous barrier recovery following acute barrier disruption, and that sedative drugs block this delay. A sedative effect of some odorants has been reported. In the present study, we demonstrate that odorant inhalation affects cutaneous barrier homeostasis in both mice and humans. Odorants with a sedative effect prevented the delay of skin barrier recovery induced by stress after acute barrier disruption. Other odorants did not show this effect.