Skin barrier function relies on three essential components: stratum corneum (SC) lipids, natural moisturizing factors (NMFs), and the acidic pH of the SC surface. Three endogenous pathways contribute ...to acidity: free fatty acids from phospholipids, trans-urocanic acid from filaggrin (FLG), and the sodium-proton antiporter (NHE1) activity. An acidic SC environment boosts the activity of enzymes to produce ceramides, which are vital for skin health. Conversely, an elevated pH can lead to increased skin infections, reduced lipid-processing enzyme activity, impaired permeability barrier recovery, and compromised integrity and cohesion of the SC due to increased serine protease (SP) activity. Elevated SC pH is observed in neonatal, aged, and inflamed skin. In atopic dermatitis (AD), it results from decreased NMF due to reduced FLG degradation, decreased fatty acids from reduced lamellar body secretion, and reduced lactic acid due to decreased sweating. Moreover, the imbalance between SP and SP inhibitors disrupts barrier homeostasis. However, acidifying the SC can help restore balance and reduce SP activity. Acidic water bathing has been found to be safe and effective for AD. In three different AD murine models, SC acidification prevented the progression of AD to respiratory allergies. In aging skin, a decrease in NHE1 leads to an increased skin pH. Mild acidic skin care products or moisturizers containing NHE1 activators can normalize skin pH and improve barrier function. In conclusion, maintaining the acidity of the SC is crucial for healthy skin barrier function, leading to significant benefits for various skin conditions, such as AD and aging-related skin issues.
1 Dermatology and Medical Services (Metabolism), Veteran Affairs Medical Center San Francisco and Department of Dermatology and Medicine, University of California San Francisco, San Francisco, ...California; and 2 Department of Dermatology, Yonsei University, Wonju College of Medicine, Wonju, Korea
Submitted 5 January 2006
; accepted in final form 17 July 2006
Many cutaneous disorders are adversely affected by psychological stress (PS), but the responsible mechanisms are poorly understood. Recent studies have demonstrated that PS decreases epidermal proliferation and differentiation, impairs permeability barrier homeostasis, and decreases stratum corneum integrity. PS also increases the production of endogenous glucocorticoids (GC), and both systemic and topical GC cause adverse effects on epidermal structure and function similar to those observed with PS. We therefore hypothesized that increased endogenous GC in PS mediates its adverse cutaneous effects. To test this hypothesis, we used two independent approaches, administering either RU-486, a GC receptor antagonist that inhibits GC action, or antalarmin, a corticotropin-releasing hormone (CRH) receptor antagonist that prevents increased GC production in the face of PS. Inhibition of either GC action or production prevents the PS-induced decline in epidermal cell proliferation and differentiation, impairment in permeability barrier homeostasis, and decrease in stratum corneum (SC) integrity. Moreover, the pathophysiological basis for the abnormality in permeability barrier homeostasis; i.e., decreased lamellar body production and secretion, is restored toward normal by inhibition of GC action. Similarly, the mechanistic basis for the decrease in SC integrity, i.e., a reduction in corneodesmosomes, is also normalized by inhibition of GC action. Thus many of the adverse effects of PS on epidermal structure and function can be attributed to increased endogenous GC and conversely, approaches that either reduce GC production or action might benefit cutaneous disorders that are provoked or exacerbated by PS.
RU-486; corticotropin-releasing hormone; stratum corneum integrity; barrier homeostasis
Address for reprint requests and other correspondence: K. R. Feingold, Veteran Affairs Medical Center, Metabolism Section (111F), 4150 Clement St., San Francisco, CA 94121 (e-mail: kfngld{at}itsa.ucsf.edu )
Stratum corneum (SC) pH regulates skin barrier functions and elevated SC pH is an important factor in various inflammatory skin diseases. Acidic topical formulas have emerged as treatments for ...impaired skin barriers. Sodium proton exchanger 1 (NHE1) is an important factor in SC acidification. We investigated whether topical applications containing an NHE1 activator could improve skin barrier functions. We screened plant extracts to identify NHE1 activators in vitro and found
leaf extract. Rosmarinic acid, a component of
leaf extract, significantly increased NHE1 mRNA expression levels and NHE1 production. Immunofluorescence staining of NHE1 in 3D-cultured skin revealed greater upregulation of NHE1 expression by NHE1 activator cream, compared to vehicle cream. Epidermal lipid analysis revealed that the ceramide level was significantly higher upon application of the NHE1 activator cream on 3D-cultured skin, compared to application of a vehicle cream. In a clinical study of 50-60-year-old adult females (
= 21), application of the NHE1 activator-containing cream significantly improved skin barrier functions by reducing skin surface pH and transepidermal water loss and increasing skin hydration, compared to patients who applied vehicle cream and those receiving no treatment. Thus, creams containing NHE1 activators, such as rosmarinic acid, could help maintain or recover skin barrier functions.
Inactive cortisone is converted into active cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier ...impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11β-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11β-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11β-HSD1 knockout mice (n = 11), 11β-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11β-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11β-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier.
We aimed to provide real-world evidence on the benefit of persistence with antiplatelet therapy (APT) on long-term all-cause mortality (ACM) in ischemic stroke patients aged 75 years and older.
Newly ...diagnosed ischemic stroke patients aged 75 years and older who initiated aspirin or clopidogrel for the first time were chosen from 2003 to 2010 National Health Insurance Service-National Sample Cohort (NHIS-NSC) of Korea (n = 887), a random cohort sample accounting for 2.2% (n = 1,017,468) of total population (n = 46,605,433). Then subjects were divided into persistent (n = 556) and non-persistent (n = 321) groups according to the persistent status at 6 months. Survivor analysis was performed between the two groups and predictors of non-persistence were analyzed by multivariate logistic regression analysis. Patients were followed up until death or December 31, 2013.
Non-persistence with APT was significantly associated with increased risk of ACM (adjusted hazard ration aHR 2.13, 95% confidence interval CI 1.72-2.65), cerebro-cardiovascular disease (CVD) mortality (aHR 2.26, 95% CI 1.57-3.24), and non-CVD mortality (aHR 2.06, 95% CI 1.5702.70). More comorbidities (Charlson comorbidity index score ≥ 6) (adjusted odds ratio aOR, 2.56, 95% CI 1.43-4.55), older age (aOR 1.52, 95% CI 1.11-2.09 for 80-84 years, aOR 1.73, 95% CI 1.17-2.57 for ≥85 years), and less than 4 total prescribed drugs (aOR 1.54, 95% CI 1.08-2.21) were independent predictors of non-persistence.
Persistent with APT after ischemic stroke featured long-term mortality benefit even in patients aged 75 years and older. Thus, improving APT persistence for ischemic stroke patients in this age group is also recommended by understanding factors associated with non-persistence.
Prolonged and/or repeated damage to the skin barrier followed by atopic dermatitis (AD) is an initial step in atopic march that ultimately progresses to respiratory allergy. Maintaining normal ...stratum corneum (SC) acidity has been suggested as a therapeutic or preventive strategy for barrier impairment caused by skin inflammation. We determined whether a representative AD murine model, NC/Nga mice, develops airway inflammation after repeated epicutaneous application followed by inhalation of house dust mite (HDM), implying atopic march, and whether prolongation of non-proper SC acidity accelerates respiratory allergy. HDM was applied to the skin of NC/Nga mice, accompanied by the application of neutral cream (pH 7.4) or acidic cream (pH 2.8) for 6weeks. Intranasal inhalation of HDM was administered daily during the last 3days. Repeated epicutaneous applications followed by inhalation of HDM in NC/Nga mice induced an atopic march-like progression from AD lesions to respiratory allergy. Concurrent neutral cream treatment accelerated or aggravated the allergic inflammation in the skin and respiratory system, whereas an acidic cream partially alleviated these symptoms. Collectively, we developed an atopic march in NC/Nga mice by HDM application, and found that prevention of a neutral environment in the SC may be an interventional method to inhibit the march.
Protease-activated receptor-2 (PAR-2) is known to be involved in epidermal permeability barrier function homeostasis. PAR-2 activation occurs after barrier disruption and further activation of PAR-2 ...by activating peptide significantly delays barrier recovery rate. Cockroach and house dust mite allergens, both known to be associated with the development of asthma, allergic rhinitis, and atopic dermatitis, have protease activity, which can activate PAR-2. In this study, we investigated the effects of both allergens on the epidermal barrier function as well as on the epidermal calcium gradient. Both allergens, when topically applied on the barrier-disrupted site, increased protease activities in the epidermis and delayed barrier recovery and lamellar body secretion in murine skin. The topical application of PAR-2-specific antagonist or protease inhibitors normalized the barrier recovery. Cockroach allergens induced intracellular calcium oscillations in cultured human keratinocytes through PAR-2-involved pathway, which was confirmed by desensitization protocol. Abnormal calcium ion distribution after barrier disruption was also observed in allergens-applied skin. These results suggest that allergens with protease activity can influence the epidermal permeability barrier homeostasis through PAR-2 activation and consequent modulation of the calcium ions in skin.
Long‐standing or repeated skin barrier damage followed by atopic dermatitis (AD) is the initial step of the atopic march that eventually progresses to respiratory allergies. Maintenance of an acidic ...pH in the stratum corneum (SC) is an important factor for normal skin barrier function. We performed this study to determine whether an oxazolone (Ox)‐induced AD murine model can develop airway inflammation by topical application and nasal inhalation of a house dust mite, Dermatofagoides pteronyssinus (Dp), which is a novel ‘atopic march animal model’, and whether an acidic SC environment, made by repeated application of acidic cream, can interrupt this atopic march. During repeated treatment with Ox and Dp to make an atopic march murine model, acidic cream (pH 2.8) and neutral cream (pH 7.4) adjusted by citric acid and sodium hydroxide mixed with vehicle were applied twice daily. Repeated treatment with Ox and Dp to hairless mice induced AD‐like skin lesions followed by respiratory allergy, defining it as an atopic march model. Acidic cream inhibited the occurrence of respiratory allergic inflammation as well as AD‐like skin lesions. These results indicate that a novel atopic march animal model can be developed by repeated topical and nasal treatments with house dust mite on Ox‐induced AD mice and that the acidification of SC could be a novel intervention method to block the atopic march.
: With the exception of vitamin D production, virtually all epidermal functions can be considered as protective, or more specifically, as defensive in nature (1). Yet, the term “barrier function” of ...the stratum corneum (SC) is often used synonymously with only one such defensive function, although arguably its most important, i.e., permeability barrier homeostasis. Regardless of their hierarchy of relative importance, these critical protective functions largely reside in the SC. In this short review, we explore the ways in which the multiple defensive functions of the SC are linked and interrelated, either by their shared localization or by common biochemical processes.
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