【开放获取】皮肤干燥是通透屏障功能受损的表现吗？

【摘要】 有学者认为,皮肤干燥是表皮通透屏障功能受损的表现,但目前尚没有足够的证据证明这一观点。实际上,皮肤干燥是角质层含水量降低的表现。角质层含水量主要由角质层天然保湿因子的量决定,而表皮通透屏障功能则主要由角质层脂质的质和量以及结构蛋白决定。如果皮肤干燥是由表皮通透屏障功能降低所致,那么,角质层含水量应当与透皮失水率呈负相关性。但是研究表明,无论是正常人皮肤、鱼鳞病皮损或皮脂腺缺乏的小鼠皮肤,角质层含水量与透皮失水率均无负相关性。相反,有研究显示,人角质层含水量与透皮失水率呈正相关性。因此,皮肤干燥似乎不是表皮通透屏障功能受损的表现。     

Glycerol regulates stratum corneum hydration in sebaceous gland deficient (asebia) mice

The only known function of human sebaceous glands is the provocation of acne. We assessed here whether sebum influences stratum corneum hydration or permeability barrier function in asebia J1 and 2 J mice, with profound sebaceous gland hypoplasia. Asebia J1 mice showed normal permeability barrier homeostasis and extracellular lamellar membrane structures, but they displayed epidermal hyperplasia, inflammation, and decreased (>50%) stratum corneum hydration, associated with a reduction in sebaceous gland lipids (wax diesters/monoesters, sterol esters). The triglyceride content of both asebia and control stratum corneum was low, consistent with high rates of triglyceride hydrolysis within the normal pilosebaceous apparatus, despite high rates of triglyceride synthesis. Although a mixture of synthetic, sebum-like lipids (sterol/wax esters, triglycerides) did not restore normal stratum corneum hydration to asebia skin, topical glycerol, the putative product of triglyceride hydrolysis in sebaceous glands, normalized stratum corneum hydration, and the glycerol content of asebia stratum corneum was 85% lower than in normal stratum corneum. In contrast, another potent endogenous humectant (urea) did not correct the abnormality. The importance of glycerol generation from triglyceride in sebaceous glands for stratum corneum hydration was demonstrated further by (i) the absence of sebaceous-gland-associated lipase activity in asebia mice, whereas abundant enzyme activity was present in the glands of control mice; and (ii) the inability of high concentrations of topical triglyceride to correct the hydration abnormality, despite the presence of abundant lipase activity in asebia stratum corneum. These results show that sebaceous-gland-derived glycerol is a major contributor to stratum corneum hydration.     

Inducible nitric oxide synthase is required for epidermal permeability barrier homeostasis in mice

Nitric oxide (NO) regulates a variety of epidermal functions, including epidermal proliferation, differentiation and cutaneous wound healing. However, whether nitric oxide (NO) and its synthetic enzymes regulate epidermal permeability barrier homeostasis is not clear. In the present study, we employed inducible nitric oxide synthase (iNOS) KO mice to explore the role of iNOS in epidermal permeability barrier homeostasis. Our results showed that iNOS mice displayed a comparable levels of basal transepidermal water loss rates, stratum corneum hydration and skin surface pH to their wild-type mice, but epidermal permeability barrier recovery was significantly delayed both 2 and 4 hours after acute barrier disruption by tape stripping. In parallel, expression levels of mRNA for epidermal differentiation-related proteins and lipid synthetic enzymes were lower in iNOS KO mice versus wild-type controls. Topical applications of two structurally unrelated NO donors to iNOS KO mice improved permeability barrier recovery kinetics and upregulated expression levels of mRNA for epidermal differentiation-related proteins and lipid synthetic enzymes. Together, these results indicate that iNOS and its product regulate epidermal permeability barrier homeostasis in mice.     

Dynamics of skin barrier repair following preconditioning by a biotechnology-driven extract from samphire (Crithmum maritimum) stem cells

Background With aging, the barrier repair kinetics following any weakening of the epidermal permeability barrier function is commonly slowed down. Objective To assess the recovery rate of the epidermal permeability barrier function following controlled stripping and applications of samphire and control formulations. Method In 12 healthy subjects older than 50 years, controlled stratum corneum (SC) strippings were used to increase the transepidermal water loss (TEWL) just above 15 g/m²/h. This procedure followed a 14‐day skin preconditioning by daily applications of formulations enriched or not with a samphire (Crithmum maritimum) biomass. An untreated skin site served as control. The epidermal permeability repair kinetics was assessed for 14 days by daily measurements of both TEWL and the colorimetric value a*. Results A rapid (96 h) recovery to lower TEWL values was obtained at each of the samphire‐preconditioned sites (0.1% serum, 0.05% cream, the serum–cream association, and 0.5% silicone oil). This process was significantly (P < 0.001) faster than that on both the placebo‐preconditioned (silicone oil) and the untreated sites. No adverse inflammatory and sensory reactions were recorded. At the sites preconditioned by samphire formulations, the SC moisture (capacitance) was higher at completion of the study compared to inclusion. Conclusions The present experimental pilot study brings some clues supporting a beneficial boosting effect of samphire cell biomass on the kinetics of epidermal permeability barrier repair.     

Aging of the skin barrier

The skin barrier is mainly present in the stratum corneum (SC), composed of corneocytes surrounded by intercellular lipid lamellae, and attached by corneodesmosome. The tight junction attached to the lateral walls of keratinocytes in the upper part of the stratum granulosum is also included in the skin barrier. During aging, the following structures and functions of the skin barrier are changed or disturbed: (1) skin barrier structure, (2) permeability barrier function, (3) epidermal calcium gradient, (4) epidermal lipid synthesis and SC lipid processing, (5) cytokine production and response after insults, (6) SC acidity, (7) SC hydration, and (8) antimicrobial barrier. Patients with diabetes also show changes in the skin barrier similar to those in aged skin, and the characteristics of the skin barrier are very similar. Understanding the pathogenic mechanisms of the skin barrier in aging will permit us to develop therapeutic strategies for aged or diabetic skin.     

Urea uptake enhances barrier function and antimicrobial defense in humans by regulating epidermal gene expression

Urea is an endogenous metabolite, known to enhance stratum corneum hydration. Yet, topical urea anecdotally also improves permeability barrier function, and it appears to exhibit antimicrobial activity. Hence, we hypothesized that urea is not merely a passive metabolite, but a small-molecule regulator of epidermal structure and function. In 21 human volunteers, topical urea improved barrier function in parallel with enhanced antimicrobial peptide (AMP; LL-37 and β-defensin-2) expression. Urea stimulates the expression of, and is transported into, keratinocytes by two urea transporters (UTs), UT-A1 and UT-A2, and by aquaporins 3, 7, and 9. Inhibitors of these UTs block the downstream biological effects of urea, which include increased mRNA and protein levels of (i) transglutaminase-1, involucrin, loricrin, and filaggrin, (ii) epidermal lipid synthetic enzymes, and (iii) cathelicidin/LL-37 and β-defensin-2. Finally, we explored the potential clinical utility of urea, showing that topical urea applications normalized both barrier function and AMP expression in a murine model of atopic dermatitis. Together, these results show that urea is a small-molecule regulator of epidermal permeability barrier function and AMP expression after transporter uptake, followed by gene regulatory activity in normal epidermis, with potential therapeutic applications in diseased skin.     

Impaired cutaneous permeability barrier function, skin hydration, and sphingomyelinase activity in keratin 10 deficient mice

Point mutations in the suprabasal cytokeratins 1 (K1) or 10 (K10) in humans have been shown to be the cause of the congenital ichthyosis epidermolytic hyperkeratosis. Recently, a K10 deficient mouse model was established serving as a model for epidermolytic hyperkeratosis. Homozygotes suffered from severe skin fragility and died shortly after birth. Heterozygotes developed hyperkeratosis with age. To see whether phenotypic abnormalities in the mouse model were associated with changes in skin barrier function and skin water content we studied basal transepidermal water loss and capacity for barrier repair after experimental barrier disruption as well as stratum corneum hydration. Also, we determined the activities of acid and neutral sphingomyelinase key enzymes of the tumor necrosis factor and interleukin-1 signal transduction pathways generating the ceramides most important for epidermal permeability barrier homeostasis. Neonatal homozygotes showed an 8-fold increase in basal transepidermal water loss compared with wild type controls. Adult heterozygotes exhibited delayed barrier repair after experimental barrier disruption. Stratum corneum hydration was reduced in homozygous and heterozygous mice. Acid sphingomyelinase activity, which is localized in the epidermal lamellar bodies and generates ceramides for extracellular lipid lamellae in the stratum corneum permeability barrier, was reduced in homozygous as well as heterozygous animals. Neutral sphingomyelinase activity, which has a different location and generates ceramides involved in cell signaling, was increased. The reduction in acid sphingomyelinase activity may explain the recently described decreased ratio of ceramides to total lipids in K10 deficient mice. In summary, our results demonstrate the crucial role of the keratin filament for permeability barrier function and stratum corneum hydration.     

Beneficial effects of pseudoceramide-containing physiologic lipid mixture as a vehicle for topical steroids

Among the various adverse effects of topical corticosteroids, impairment of the epidermal permeability barrier is well-known. Decreased synthesis of the epidermal lipid consequently leads to structural defects of the stratum corneum. Recently, the beneficial effects of physiologic lipid mixtures containing pseudoceramide on the impaired epidermal permeability barrier have been reported, which suggest that physiologic lipid mixtures may reduce the topical glucocorticoid-induced barrier impairment. In this study, the effect of a pseudoceramide-containing physiologic lipid mixture as a vehicle for a mid-potency topical glucocorticoid was evaluated in an oxazolone-induced atopic dermatitis-like murine model. The changes in transepidermal water loss, hydration and skin fold thickness were measured. Inflammatory cells in the dermis, including eosinophils, were counted and Staphylococcus aureus binding assay was performed. Immunohistochemical staining for inflammatory cytokines and antimicrobial peptides were also performed. The topical steroid in physiologic lipid mixture showed a significantly decreased infiltrate of inflammatory cells (p<0.05) and a reduced number of adherent Staphylococcus aureus compared with the results of the topical steroid in polyethylene glycol/ethanol vehicle (p<0.05). In conclusion, the pseudoceramide-containing physiologic lipid mixture as a vehicle for a topical steroid enhanced the anti-inflammatory effect of the topical steroid and accelerated the skin barrier function restoration.     

Dietary glucosylceramide improves skin barrier function in hairless mice

BACKGROUND: Sphingolipids are known to play an important role in both water retention and epidermal permeability barrier function in mammalian stratum corneum. However, little is known about the effects on epidermal function of orally administered sphingolipids. OBJECTIVE: We examined the effect of dietary glucosylceramide (GluCer) on the maintenance and recovery of epidermal barrier function. METHODS: Hairless mice were fed a particular diet (HR-AD) for 4 weeks to induce chronic skin perturbation. Subsequently, a normal diet supplemented with GluCer (from rice bran and germ) was provided for the next 4 weeks. Transepidermal water loss (TEWL) and stratum corneum flexibility were measured throughout this recovery phase. Additional hairless mice were fed a diet with or without a maize-extracted GluCer supplement for 5 weeks, then their skin was acutely perturbed with repeated tape-stripping, and the TEWL was measured. RESULTS: Although skin functions were generally lower following chronic perturbation, in GluCer-fed mice the TEWL was significantly reduced at 2 weeks and the stratum corneum flexibility was increased at 3 weeks compared to controls. Following acute barrier perturbation by tape-stripping, mice an HR-AD fed a GluCer diet exhibited enhanced recovery compared with the control diet group. CONCLUSION: These results demonstrate that in hairless mice skin barrier functions impaired by chronic or acute perturbations were improved by dietary GluCer. The oral administration of GluCer may be useful for the preservation and recovery of epidermal barrier functions an HR-AD.     

The 24‐hr, 28‐day,and 7‐day post‐moisturizing efficacy of ceramides 1, 3, 6‐II containing moisturizing cream compared with hydrophilic cream on skin dryness and barrier disruption in senile xerosis treatment

Direct replacement of decreased ceramides in the stratum corneum can be efficacious for skin hydration, skin barrier function, and skin pH. Our study aimed to evaluate the 24‐hr, 28‐day, and 7‐day post‐moisturizing efficacy of ceramide‐containing moisturizer in senile xerosis treatment. A split site, double‐blinded, randomized, controlled study was conducted in 24 senile subjects (91.7% females, mean age 54.83 ± 5.45 years) with mild to moderate xerosis, who were randomized to receive ceramide‐containing moisturizer or hydrophilic cream, daily applied on each side of the shin. A single application of ceramide‐containing moisturizer increased skin hydration, while improving transepidermal water loss (TEWL) and skin pH for up to 24 hr, with statistically significant difference. After 28 days of twice‐daily application, more significant improvement on skin hydration, barrier function, and skin pH was observed in those with ceramide‐containing moisturizer at all‐time points. At day 28, there was a statistically significant decrease of hemoglobin index, wrinkle, and texture on the ceramide treated side. The 7‐day post‐moisturizing efficacy on the ceramide treated side was superior for skin hydration, TEWL, skin pH, and wrinkle. Thus, the ceramide‐containing moisturizer can be a novel promising treatment for senile xerosis.     

Stratum corneum and nail lipids in patients with atopic dermatitis. Decrease in ceramides--a pathogenetic factor in atopic xerosis?

Dry skin is seen in many patients with atopic dermatitis and correlates with a disturbed epidermal barrier function demonstrated by such features as increased transepidermal water loss and diminished stratum corneum hydration. With regard to the importance of stratum corneum lipids for the permeability barrier, we have analysed plantar (n = 8) and lumbar (n = 20) stratum corneum and nail lipids (n = 15) of atopic subjects by high-performance thin-layer chromatography (HPTLC). Compared with controls our investigations show a decrease in the ceramide fraction as a percentage of total lipid and a diminished ratio of ceramides and free sterols in atopic subjects. This implies that impaired ceramide synthesis may be a factor in the pathogenesis of atopic xerosis.     

Topical hesperidin prevents glucocorticoid‐induced abnormalities in epidermal barrier function in murine skin

Systemic and topical glucocorticoids (GC) can cause significant adverse effects not only on the dermis, but also on epidermal structure and function. In epidermis, a striking GC‐induced alteration in permeability barrier function occurs that can be attributed to an inhibition of epidermal mitogenesis, differentiation and lipid production. As prior studies in normal hairless mice demonstrated that topical applications of a flavonoid ingredient found in citrus, hesperidin, improve epidermal barrier function by stimulating epidermal proliferation and differentiation, we assessed here whether its topical applications could prevent GC‐induced changes in epidermal function in murine skin and the basis for such effects. When hairless mice were co‐treated topically with GC and 2% hesperidin twice‐daily for 9 days, hesperidin co‐applications prevented the expected GC‐induced impairments of epidermal permeability barrier homoeostasis and stratum corneum (SC) acidification. These preventive effects could be attributed to a significant increase in filaggrin expression, enhanced epidermal β‐glucocerebrosidase activity and accelerated lamellar bilayer maturation, the last two likely attributable to a hesperidin‐induced reduction in stratum corneum pH. Furthermore, co‐applications of hesperidin with GC largely prevented the expected GC‐induced inhibition of epidermal proliferation. Finally, topical hesperidin increased epidermal glutathione reductase mRNA expression, which could counteract multiple functional negative effects of GC on epidermis. Together, these results show that topical hesperidin prevents GC‐induced epidermal side effects by divergent mechanisms.     

Glycerol and the skin: holistic approach to its origin and functions

Glycerol is a trihydroxy alcohol that has been included for many years in topical dermatological preparations. In addition, endogenous glycerol plays a role in skin hydration, cutaneous elasticity and epidermal barrier repair. The aquaporin-3 transport channel and lipid metabolism in the pilosebaceous unit have been evidenced as potential pathways for endogenous delivery of glycerol and for its metabolism in the skin. Multiple effects of glycerol on the skin have been reported. The diverse actions of the polyol glycerol on the epidermis include improvement of stratum corneum hydration, skin barrier function and skin mechanical properties, inhibition of the stratum corneum lipid phase transition, protection against irritating stimuli, enhancement of desmosomal degradation, and acceleration of wound-healing processes. Even an antimicrobial effect has been demonstrated. Topical application of glycerol-containing products improves skin properties in diseases characterized by xerosis and impaired epidermal barrier function, such as atopic dermatitis. The increase of epidermal hydration by glycerol is critical in skin conditions aggravated by dry and cold environmental conditions, e.g. winter xerosis. This paper provides a review on effects of glycerol on the skin, the mechanisms of its action, and the potential applications of glycerol in dermatology.     

The influence of stratum corneum hydration on body fat determination by bioelectrical impedance analysis

Background/aims: Bioelectrical impedance analysis (BIA) is used for the estimation of the amount of body fat. We evaluated the influence of the stratum corneum hydration at the contact areas used for BIA on the body fat estimation. Methods: Stratum corneum hydration was measured at the sole of the right foot and the palm of the right hand before and after contact with the Tanita Body Composition Analyzer TBF 410^® and the Omron Body Fat Analyzer^®, (n=128 females and 126 males), respectively. Changes in stratum corneum hydration during the contact time were calculated (ΔHYD). As a gold standard for body fat estimation, the underwater weighing method (UWW) was used and the deviation of this standard was calculated for the Tanita (DT) and the Omron (DO) measurement. Results: During contact with the Tanita, stratum corneum hydration increased significantly at the foot. Neither stratum corneum hydration measured at the respective contact sites before BIA nor ΔHYD at the respective skin sites was related to DT or with DO. Conclusion: The BIA measuring procedure using the Tanita instrument leads to an occlusive effect at the contact site. BIA for the determination of body composition is not influenced by stratum corneum hydration.     

IL‐6 Stimulates but is not essential for stratum corneum formation and permeability barrier development during gestation

Please cite this paper as: IL‐6 Stimulates but is not essential for stratum corneum formation and permeability barrier development during gestation. Experimental Dermatology 2010; 19 : e31–e36. Abstract: The regulation of epidermal ontogenesis is a complex process. Previous studies have shown that cytokines (IL‐1, TNFα and IL‐6) regulate permeability barrier homeostasis in adult mice. Recently, we reported that IL‐1 and TNFα accelerate stratum corneum (SC) formation and permeability barrier development in foetal rodents. Here, we determined whether IL‐6 also regulates SC formation and permeability barrier development during late gestation. Using a rat skin explant model, we demonstrated that IL‐6 accelerates permeability barrier formation in a time‐ and dose‐dependent fashion. This acceleration of barrier formation is attributable to (a) accelerated lamellar membrane maturation, (b) formation of a multi‐layer SC and (c) enhanced expression of epidermal differentiation markers. When comparing epidermis of IL‐6‐deficient (knockout mice) and wild‐type foetal mice at days 16–18, we could not detect any abnormalities in either SC formation or the expression of differentiation markers in knockout (KO) mice. In parallel, the basal expression levels of IL‐6 mRNA in epidermis and IL‐6 protein in amniotic fluid were very low, with only a minimal change in IL‐6 receptor mRNA levels in epidermis of days 16–22 foetal mice. These low IL‐6 levels may account, at least in part, for the absence of epidermal abnormalities in IL‐6 KO mice. In conclusion, exogenous IL‐6 accelerates epidermal ontogenesis, but it is not essential for normal epidermal maturation.     

Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity: inhibition of epidermal lipid synthesis accounts for functional abnormalities

Prolonged exposure of human epidermis to excess endogenous or exogenous glucocorticoids can result in well-recognized cutaneous abnormalities. Here, we determined whether short-term glucocorticoid treatment would also display adverse effects, specifically on two key epidermal functions, permeability barrier homeostasis and stratum corneum integrity and cohesion, and the basis for such changes. In humans 3 d of treatment with a potent, commonly employed topical glucocorticoid (clobetasol), applied topically, produced a deterioration in barrier homeostasis, characterized by delayed barrier recovery and abnormal stratum corneum integrity (rate of barrier disruption with tape strippings) and stratum corneum cohesion (microg protein removed per stripping). Short-term systemic and topical glucocorticoid produced similar functional defects in mice, where the basis for these abnormalities was explored further. Both the production and secretion of lamellar bodies were profoundly decreased in topical glucocorticoid-treated mice resulting in decreased extracellular lamellar bilayers. These structural changes, in turn, were attributable to a profound global inhibition of lipid synthesis, demonstrated both in epidermis and in cultured human keratinocytes. The basis for the abnormality in stratum corneum integrity and cohesion was a diminution in the density of corneodesmosomes in the lower stratum corneum. We next performed topical replacement studies to determine whether lipid deficiency accounts for the glucocorticoid-induced functional abnormalities. The abnormalities in both permeability barrier homeostasis and stratum corneum integrity were corrected by topical applications of an equimolar distribution of free fatty acids, cholesterol, and ceramides, indicating that glucocorticoid-induced inhibition of epidermal lipid synthesis accounts for the derangements in both cutaneous barrier function and stratum corneum integrity/cohesion. These studies indicate that even short-term exposure to potent glucocorticosteroids can exert profound negative effects on cutaneous structure and function. Finally, topical replenishment with epidermal physiologic lipids could represent a potential method to reduce the adverse cutaneous effects of both topical glucocorticoid treatment and Cushing's syndrome.     

Influence of skin type, race, sex, and anatomic location on epidermal barrier function

The intact skin represents a barrier to the uncontrolled loss of water, proteins, and plasma components from the organism. Owing to its complex structure, the epidermal barrier with its major layer, the stratum corneum, is the rate-limiting unit for the penetration of exogenous substances through the skin. The epidermal barrier is not a static structure. The status of different functions of the epidermis can be monitored by assessing specific biophysical parameters such as transepidermal water loss, stratum corneum hydration, and skin surface pH. Variables originating from the individual as well as exogenous factors have an important influence on the epidermal barrier parameters.     

Generation of free fatty acids from phospholipids regulates stratum corneum acidification and integrity.

There is evidence that the "acid mantle" of the stratum corneum is important for both permeability barrier formation and cutaneous antimicrobial defense. The origin of the acidic pH of the stratum corneum remains conjectural, however. Both passive (e.g., eccrine/sebaceous secretions, proteolytic) and active (e.g., proton pumps) mechanisms have been proposed. We assessed here whether the free fatty acid pool, which is derived from phospholipase-mediated hydrolysis of phospholipids during cornification, contributes to stratum corneum acidification and function. Topical applications of two chemically unrelated secretory phospholipase sPLA2 inhibitors, bromphenacylbromide and 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol, for 3 d produced an increase in the pH of murine skin surface that was paralleled not only by a permeability barrier abnormality but also altered stratum corneum integrity (number of strippings required to break the barrier) and decreased stratum corneum cohesion (protein weight removed per stripping). Not only stratum corneum pH but also all of the functional abnormalities normalized when either palmitic, stearic, or linoleic acids were coapplied with the inhibitors. Moreover, exposure of intact murine stratum corneum to a neutral pH for as little as 3 h produced comparable abnormalities in stratum corneum integrity and cohesion, and further amplified the inhibitor-induced functional alterations. Furthermore, short-term applications of an acidic pH buffer to inhibitor-treated skin also reversed the abnormalities in stratum corneum integrity and cohesion, despite the ongoing decrease in free fatty acid levels. Finally, the secretory-phospholipase-inhibitor-induced alterations in integrity/cohesion were in accordance with premature dissolution of desmosomes, demonstrated both by electron microscopy and by reduced desmoglein 1 levels in the stratum corneum (shown by immunofluorescence staining and visualized by confocal microscopy). Together, these results demonstrate: (i) the importance of phospholipid-to-free-fatty-acid processing for normal stratum corneum acidification; and (ii) the potentially important role of this pathway not only for barrier homeostasis but also for the dual functions of stratum corneum integrity and cohesion.     

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。