Article

Skin Barrier Disruption by Sodium Lauryl Sulfate-Exposure Alters the Expressions of Involucrin, Transglutaminase 1, Profilaggrin, and Kallikreins during the Repair Phase in Human Skin In Vivo

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Abstract

Detergents are skin irritants affecting keratinocytes. In this study, healthy volunteers were exposed to water (vehicle) and 1% sodium lauryl sulfate (SLS) under occlusive patch tests for 24 hours. The messenger RNA (mRNA) expression of keratinocyte differentiation markers and of enzymes involved in corneodesmosome degradation was examined in skin biopsies (n=8) during the repair phase (6 hours to 7 days postexposure) using real-time reverse-transcription PCR. It was found that the expression of involucrin was increased at 6 hours, but then rapidly normalized. The expression of transglutaminase 1 exhibited a twofold increase after 24 hours in the SLS-exposed skin. Profilaggrin was decreased after 6 hours. Later (4-7 days), the expression in SLS-exposed areas was >50% above than in control areas. An increased and altered immunofluorescence pattern of involucrin, transglutaminase 1, and filaggrin was also found (n=4). At 6 hours post-SLS exposure, the mRNA expression of kallikrein-7 (KLK-7) and kallikrein-5 (KLK-5) was decreased by 50 and 75%, respectively, as compared with control and water-exposed areas. Thereafter, the expression pattern of KLK-7 and KLK-5 was normalized. Changes in protein expression of KLK-5 were also found. In conclusion, SLS-induced skin barrier defects induce altered mRNA expression of keratinocyte differentiation markers and enzymes degrading corneodesmosomes.

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... Detergents in personal care products can exacerbate skin barrier dysfunction. 32,34,35 In dermatology research, the detergent sodium dodecyl sulfate, which is the same compound as sodium laurel sulfate in household detergents, has been used to aid in absorption of compounds into skin in research studies. 36 ...
... 13,14 The detergent is necessary for the skin exposure, because it aids in skin absorption of the allergen in saline. Detergents disrupt keratinocyte barrier 34,35 and increase trans-epidermal water loss (TEWL). [45][46][47] Without the detergent, when the solution of allergen in saline is placed on the pups skin, it rolls off the pups skin and onto the surface under the pup. ...
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Food allergy can be life‐threatening and often develops early in life. In infants and children, loss‐of‐function mutations in skin barrier genes associate with food allergy. In a mouse model with skin barrier mutations (Flakey Tail, FT+/− mice), topical epicutaneous sensitization to a food allergen peanut extract (PNE), an environmental allergen Alternaria alternata (Alt) and a detergent induce food allergy and then an oral PNE‐challenge induces anaphylaxis. Exposures to these allergens and detergents can occur for infants and children in a household setting. From the clinical and preclinical studies of neonates and children with skin barrier mutations, early oral exposure to allergenic foods before skin sensitization may induce tolerance to food allergens and thus protect against development of food allergy. In the FT+/− mice, oral food allergen prior to skin sensitization induce tolerance to food allergens. However, when the skin of FT+/− pups are exposed to a ubiquitous environmental allergen at the time of oral consumption of food allergens, this blocks the induction of tolerance to the food allergen and the mice can then be skin sensitized with the food allergen. The development of food allergy in neonatal FT+/− mice is mediated by altered skin responses to allergens with increases in skin expression of interleukin 33, oncostatin M and amphiregulin. The development of neonate food allergy is enhanced when born to an allergic mother, but it is inhibited by maternal supplementation with α‐tocopherol. Moreover, preclinical studies suggest that food allergen skin sensitization can occur before manifestation of clinical features of atopic dermatitis. Thus, these parameters may impact design of clinical studies for food allergy, when stratifying individuals by loss of skin barrier function or maternal atopy before offspring development of atopic dermatitis.
... Consequently, a deficiency in filaggrin expression in the stratum corneum of the skin epidermis could lead to impaired skin barrier functions and an exacerbation of non-lesion atopic dermatitis [50,52,53]. Tö Rmä and colleagues demonstrated that the exposure of eleven healthy volunteers to 50 µL of 1% (v/v) SLES for six h significantly reduced the expression of pro-filaggrin in human keratinocytes [54]. In the present study, a non-significant effect of both Acidic SL and SLES on FLG expression was reported. ...
... In the present study, a non-significant effect of both Acidic SL and SLES on FLG expression was reported. The difference in dose-response in the present study compared to the report by Tö Rmä and colleagues could be explained by the difference in the concentration of SLES utilised (0.01% versus 1% (v/v)) [54]. This notwithstanding, the results reported in the current study suggest that at the tested concentration, Acidic SL may have non-deleterious effects on the architectural structure of the human skin epidermis and on the barrier functions of the human skin comparable to SLES. ...
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Acidic sophorolipids (Acidic SL), congeners of sophorolipid biosurfactants, offer a potential alternative to synthetic sodium lauryl ether sulphate (SLES) in skincare applications. However, major challenges associated with the laboratory-based investigations of the cytotoxic effects of Acidic SL have been the utilisation of impure and/or poorly characterised congeners as well as the use of monolayers of skin cells in in vitro assays. While the former limitation makes glycolipids less attractive for use in academic research and skincare applications, the latter does not provide an accurate representation of the in vivo human skin. The present study, therefore, for the first time, assessed the cytotoxic effects of 96% pure Acidic SL on a 3D in vitro skin model in comparison with SLES, with the aim of investigating a natural alternative to synthetic surfactants for potential use in skincare applications. The 3D in vitro skin model was colonised with Staphylococcus epidermidis for 12 h, and afterwards treated with either Acidic SL or SLES at 100 μg mL−1 for a further 12 h. Subsequently, the cytotoxic effects of Acidic SL in comparison with SLES were assessed using a combination of microbiology, molecular biology techniques, immunoassays, and histological analyses. It was demonstrated that Acidic SL had no deleterious effects on the viability of S. epidermidis, tissue morphology, filaggrin expression, and the production of inflammatory cytokines in comparison to SLES. These findings, in conjunction with the possibility to produce Acidic SL from cheaper renewable natural resources, demonstrate that Acidic SL could offer a potential sustainable alternative to synthetic surfactants.
... Indeed, SA and other fatty acids in Delta-5 including linoleic acid (42%) and potentially its 2-carbon elongation product 20:2n-6 (11%) via retroconversion may be incorporated into keratinocyte membranes [1]. Increases in lipid synthesis and lamellar body secretions are generally accepted to improve skin barrier function and permeability [45].SLS alters the repair phase of human skin via alteration of keratinocyte differentiation markers, and changes in enzymes degrading corneodesmosomes (intercellular adhesive structures in the stratum corneum) [46]. Following SLS-damage, fatty acid transport is increased by epidermal cytosolic fatty acid binding proteins [47], increasing fatty acids such as those present in Delta-5 in extracellular spaces. ...
... We did not know a priori what sample size would be appropriate, but the data obtained herein, will be useful for future sample size calculations in more elaborate, future studies. As a first pilot study, our strategy was to maximize potential to observe statistically significant results, albeit with caveats including a limited number of subjects (n = 7) who were not diverse (Caucasian females aged [45][46][47][48][49][50][51][52][53][54][55][56][57][58]. In males, and persons with a tougher skin surface, there would possibly be less damage with SLS, but we would still expect Delta-5 to be effective; this would need to be tested empirically. ...
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Background Sciadonic acid (SA) is an anti-inflammatory fatty acid displacing arachidonic acid (ARA) from specific phospholipid pools, thus modulating downstream pro-inflammatory lipid mediators. Its novel anti-inflammatory actions have been studied in vitro, in pre-clinical models, and stemming from testimonials, after topical- and oral application. It has not been tested in a formal clinical study for topical benefits previously. Skin barrier layer was our focus as it has a critically important role in maintaining skin moisture balance. Methods Herein, forearm skin was left undamaged; or barrier layer was chemically-damaged with 2% sodium lauryl sulfate (SLS) for 24 h. SLS-damaged skin was left untreated or treated with Delta-5® oil containing 24% SA twice daily for 27 days. Barrier function was assessed by open chamber transepidermal water loss (TEWL) and skin surface impedance on days 0 (clear skin), -1 (1-day post-SLS), -2 (2-days post-SLS, 1-day post-Delta-5), -3, -7, and − 28. Results Relative to day 1, Delta-5 oil statistically significantly decreased TEWL vs. untreated damaged sites, on days 3 (125% more reduced), -7 (74% more reduced), and − 28 (69% more reduced). Decreases in TEWL following chemical damage indicates improved skin barrier repair and healing. Similar patterns were quantified for skin impedance. There was also reduced redness observed on days 3 and − 7 with Delta-5 oil vs. untreated SLS-damaged skin. Conclusions Delta-5 oil thus has anti-inflammatory potential in human skin, under controlled clinical conditions, to accelerate irritant-induced healing, and improve skin barrier function. Improvement in barrier function would benefit dermatitis, acne, eczema, and skin scarring. In normal skin, Delta-5 oil has potential to promote healthy, moisturized skin; and improve skin structure, elasticity, and firmness.
... They can pass the layered structure formed by amphiphilic simplified models. The EU ban on animal testing forced the development of new alternative methods for assessing the skin-irritation potential [34]. Thus, for preliminary studies of the irritation potential of (bio)surfactants intended for use in cosmetic products, their effect on the model lipid bilayers of liposomes, or cytotoxicity tests towards the cultured skin cells are employed [35,36]. ...
... The human tests should be, however, preceded by simpler assays with simplified models. The EU ban on animal testing forced the development of new alternative methods for assessing the skin-irritation potential [34]. Thus, for preliminary studies of the irritation potential of (bio)surfactants intended for use in cosmetic products, their effect on the model lipid bilayers of liposomes, or cytotoxicity tests towards the cultured skin cells are employed [35,36]. ...
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Our skin is continuously exposed to different amphiphilic substances capable of interaction with its lipids and proteins. We describe the effect of a saponin-rich soapwort extract and of four commonly employed synthetic surfactants: sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), ammonium lauryl sulfate (ALS), cocamidopropyl betaine (CAPB) on different human skin models. Two human skin cell lines were employed: normal keratinocytes (HaCaT) and human melanoma cells (A375). The liposomes consisting of a dipalmitoylphosphatidylcholine/cholesterol mixture in a molar ratio of 7:3, mimicking the cell membrane of keratinocytes and melanoma cells were employed as the second model. Using dynamic light scattering (DLS), the particle size distribution of liposomes was analyzed before and after contact with the tested (bio)surfactants. The results, supplemented by the protein solubilization tests (albumin denaturation test, zein test) and oil emulsification capacity (using olive oil and engine oil), showed that the soapwort extract affects the skin models to a clearly different extent than any of the tested synthetic surfactants. Its protein and lipid solubilizing potential are much smaller than for the three anionic surfactants (SLS, ALS, SLES). In terms of protein solubilization potential, the soapwort extract is comparable to CAPB, which, however, is much harsher to lipids.
... For example, both SLS and NaOH are alkaline TABLE 1 Erythema (a* value), transepidermal water loss (TEWL) and capacitance at baseline and 24 and 96 hours after repeated exposure to acetic acid (AcA), n-propanol, sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), and distilled water (aq.) (N = 8) substances that cause elevated skin pH and might decrease the activity of the enzymes involved in filaggrin proteolysis. 26,27 However, Koppes et al observed increased activity of two key enzymes involved in filaggrin proteolysis, bleomycin hydrolase and calpain-1, after exposure to SLS in the human skin in vivo. 3 On the other hand, SLS is known to denature proteins of the cornified envelope and increase its permeability, 28 which may lead to the leakage of NMF components from the corneocytes. ...
... 3 On the other hand, SLS is known to denature proteins of the cornified envelope and increase its permeability, 28 which may lead to the leakage of NMF components from the corneocytes. 27 A similar mechanism is also likely to explain the effects of a strong corrosive agent with an alkaline pH, such as NaOH. 14,29 Further evidence that the reduction in NMF levels may be caused by skin barrier damage is provided by the finding of increased plasmin activity after exposure to SLS. 3 Elevated plasmin activity has previously been associated with a damaged skin barrier. ...
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Background Recently, natural moisturizing factors (NMFs) and corneocyte surface topography were suggested as biomarkers for irritant dermatitis. Objectives To investigate how exposure to different irritants influences corneocyte surface topography, NMF levels and the barrier function of human skin in vivo. Methods Eight healthy adult volunteers were exposed to aqueous solutions of 60% n‐propanol, 0.5% sodium lauryl sulfate (SLS), 0.15% sodium hydroxide, and 2.0% acetic acid, and distilled water, in a repeated irritation test over a period of 96 hours. Erythema, transepidermal water loss (TEWL), skin hydration, the dermal texture index (DTI) and NMF levels were measured at baseline, and after 24 and 96 hours. Results SLS and sodium hydroxide had the most pronounced effects on erythema and TEWL. Although n‐propanol caused only slight changes in TEWL and erythema, it showed pronounced effects on skin hydration, NMF levels, and the DTI. NMF was the only parameter that was significantly altered by all investigated irritants. The changes in the DTI were inversely associated with NMF levels and skin hydration. Conclusion Skin barrier impairment and the inflammatory response are irritant‐specific, emphasizing the need for a multiparametric approach to the study of skin irritation. NMF levels seem to be the most sensitive parameter in detecting irritant‐induced skin barrier alterations.
... These facts are consistent with previous reports. 25,26 However, to understand the precise mechanism, further in-depth research based on the results of this study is necessary. ...
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Objectives Skin barrier disruption is a significant problem of the older population in an aging society. It is characterized by increased transepidermal water loss and decreased skin water content, and particulate matter (PM) is a social issue that can contribute to the exacerbation of skin inflammation. Thus, addressing this problem is urgent. Methods Skin barrier‐disrupted mouse models were induced by two methods using acetone application or tape‐stripping. This study investigated the antioxidative and anti‐inflammatory properties of the Siegesbeckia herba extract (SHE) on PM‐induced changes in skin barrier‐disrupted mouse models. To examine changes in skin water content, inflammatory cytokines, and keratinocyte differentiation markers, mouse models were treated with vehicle 100 μL, PM10 100 μL (100 μg/mL), SHE 100 μL, or PM10 100 μL (100 μg/mL) plus SHE 100 μL. Results SHE preserved skin hydration in the skin barrier‐disrupted mouse models regardless of the presence of PM10. SHE also inhibited the upregulation of inflammatory cytokines such as interleukin (IL)‐1β, IL‐4, IL‐6, IL‐8, and tumor necrosis factor‐α and normalized the downregulation of keratinocyte differentiation markers against PM10 in skin barrier‐disrupted mouse models. Conclusions This study elucidated the therapeutic effects of SHE against PM10 in skin barrier‐disrupted mouse models.
... Propionibacterium spp., Corynebacterium spp., and Micrococcus spp.) and resulting in skin disease; increased in sensitisation reaction in seborrheic dermatitis patients; and may lead to the development of benign, premalignant, or malignant tumour, morphological change of epithelium cells, organ toxicity (predominantly heart, liver, lungs, and brain), ophthalmic irritation, cataract formation, carcinogenic effect, and hair loss upon long term exposure. [7][8][9][10][11][12][13][14][15][16][17] Cocamidopropyl Betaine (CAPB) Surfactant Increased the prevalence rates of allergic contact dermatitis among young children after exposure to baby shampoos containing CAPB; cosmetic-allergic patients experienced scalp itching, inflammation on the ears, neck, and forehead, and developed eczema on the face and neck; and caused dermatological sensitisation upon exposure to impurities in CAPB, such as 3-dimethylaminopropylamine (DMAPA) and amidoamine (AA). ...
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Hair shampoos containing botanical ingredients without synthetic additives, such as parabens, petrochemicals, sulfates and silicones are more skin- and environmentally friendly. In recent years, there is a growing demand for shampoo products with botanical extracts. Shampoos with botanical extracts are well-known for their perceived health benefits. They are also generally milder, non-toxic, natural, and less likely to disrupt the hair and scalp's natural pH and oil balance. Many also believe that shampoos with botanical origins have higher standards of quality. Numerous botanical extracts had been used as natural active ingredients in cosmetic formulations to meet consumer demands. In this review, we have revisited six tropical plants commonly added as natural active ingredients in shampoo formulations: Acacia concinna, Camellia oleifera, Azadirachta indica, Emblica officinalis, Sapindus mukorossi, and Garcinia mangostana. These plants have been traditionally used for hair care, and scientific research has shown that they exhibit relevant physicochemical properties and biological activities that are beneficial for hair care and scalp maintenance.
... Such a process takes place both in eczematous lesions and normal-appearing lesional skin. Detergents are responsible for increasing the release of pro-inflammatory cytokines and proteolytic enzymes [33]. Overuse of detergents and soaps negatively affects the skin by disrupting the regulation of PAR-2 receptors that are closely involved in the pathomechanism of pruritus in AD [34]. ...
... Deposition of sodium lauryl sulfate on the skin is enhanced in hard water and has been demonstrated to alter the expression of involucrin, transglutaminase 1, profilaggrin and kallikreins, thereby inducing barrier defects. 114 Additionally, a randomized controlled trial of water softener installation in an attempt to prevent AD is ongoing, with pilot trial results reporting a trend towards lower rates of physician diagnosed AD in infants in the intervention arm. 115 ...
Article
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Atopic dermatitis is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% of adults. One critical component in the pathophysiology of atopic dermatitis is the epidermal skin barrier, with its outermost layer- the stratum corneum (SC) being conferring biochemical properties that enable resilience against environmental threats and maintain homeostasis. The skin barrier may be conceptualized as a key facilitator of complex interactions between genetics, host immunity, the cutaneous microbiome, and environmental exposures. The key genetic risk factor for AD development and persistence is a loss of function mutation in filaggrin (FLG), with recent advances in genomics focusing on rare variant discovery, establishment of pathogenic mechanisms and exploration of the role of other epidermal differentiation complex gene variants in AD. Aberrant type 2 inflammatory responses downregulate the transcription of key epidermal barrier genes, alter the composition of SC lipids and induce further injury via a neuro-cutaneous feedback loop and the itch-scratch cycle. The dysbiotic epidermis exhibits reduced bacterial diversity and enhanced colonization with Staphylococcus and Malassezia species, which contribute to both direct barrier injury via the action of bacterial toxins and to perpetuation of the inflammatory cascades. Enhanced understanding of each of the pathogenic mechanisms underpinning barrier disruption has led to the development of novel topical and systemic molecules, including IL-4Ra, IL-13, PDE4 and JAK inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim to summarise the current understanding of the above pathophysiologic and therapeutic mechanisms, with a focus on the genetic, cellular and molecular mechanisms underpinning AD development.
... Additionally, SDS increases intracellular reactive oxygen species (ROS) and IL-1α secretion by human keratinocytes by increasing intracellular calpain activity and intracellular Ca 2+ concentration, promoting prostaglandin E3 (PGE3) release [47,48]. Notably, SDS also alters expression of proteases and S100 proteins, including filaggrin, in keratinocytes [49]. ...
Article
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Purpose of Review The prevalence and incidence of allergic disease have been rising in Westernized countries since the twentieth century. Increasingly, evidence suggests that damage to the epithelium initiates and shapes innate and adaptive immune responses to external antigens. The objective of this review is to examine the role of detergents as a potential risk factor for developing allergic disease. Recent Findings Herein, we identify key sources of human detergent exposure. We summarize the evidence suggesting a possible role for detergents and related chemicals in initiating epithelial barrier dysfunction and allergic inflammation. We primarily focus on experimental models of atopic dermatitis, asthma, and eosinophilic esophagitis, which show compelling associations between allergic disease and detergent exposure. Mechanistic studies suggest that detergents disrupt epithelial barrier integrity through their effects on tight junction or adhesion molecules and promote inflammation through epithelial alarmin release. Summary Environmental exposures that disrupt or damage the epithelium may account for the increasing rates of allergic disease in genetically susceptible individuals. Detergents and related chemical compounds represent possible modifiable risk factors for the development or exacerbation of atopy.
... 28 The irradiated skin at elevated levels also had increased levels of transglutaminase, which is a hallmark of compromised skin barrier as previously demonstrated in a SLS-challenged skin model. 29 The functional implications to the changes to transglutaminase has also been illustrated in patients suffering from atopic dermatitis (AD) and psoriasis, where lesional tissues marked increase in both TGM1 and TGM3. 5,6 The observed similarities in skin barrier changes following UV exposure with patients suffering from skin disorders further illustrates the importance of adequate photoprotection to prevent the alteration of barrier structure after receiving extended sunlight exposure. ...
... Four TGM family members, TGM1, TGM2, TGM3, and TGM5, are expressed in the epidermis and catalyze the formation of isopeptide bonds to construct a cornified envelope [11]. A previous study demonstrated that the expression of TGM1 was enhanced by detergent-induced barrier disruption, suggesting that the enzyme is important for maintaining the physical barrier in the epidermis [12]. Another study showed that the application of retinol improved photo-aged skin conditions by upregulating TGM1 expression [13]. ...
... 28 The irradiated skin at elevated levels also had increased levels of transglutaminase, which is a hallmark of compromised skin barrier as previously demonstrated in a SLS-challenged skin model. 29 The functional implications to the changes to transglutaminase has also been illustrated in patients suffering from atopic dermatitis (AD) and psoriasis, where lesional tissues marked increase in both TGM1 and TGM3. 5,6 The observed similarities in skin barrier changes following UV exposure with patients suffering from skin disorders further illustrates the importance of adequate photoprotection to prevent the alteration of barrier structure after receiving extended sunlight exposure. ...
... The condition has also been simulated experimentally by applying a solution of SDS to the skin [86]. With humans, a 24-h treatment with 1% SDS caused expression of profilaggrin to decrease dramatically but then increase over controls after 4 days post-treatment [87]. Application of 17% SDS for 7 h caused the epidermis to become leaky, after which restoration of the surface barrier was studied by measurement of the transepidermal water loss (TEWL) during treatment with ceramide mixtures [88]. ...
Article
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Keratohyalin granules were discovered in the mid-19th century in cells that terminally differentiate to form the outer, cornified layer of the epidermis. The first indications of the composition of these structures emerged in the 1960s from a histochemical stain for histidine, followed by radioautographic evidence of a high incidence of histidine incorporation into newly synthesized proteins in cells containing the granules. Research during the next three decades revealed the structure and function of a major protein in these granules, which was initially called the ‘histidine-rich protein’. Steinert and Dale named the protein ‘filaggrin’ in 1981 because of its ability to aggregate keratin intermediate filaments. The human gene for the precursor, ‘profilaggrin,’ was reported in 1991 to encode 10, 11 or 12 nearly identical repeats. Remarkably, the mouse and rat genes encode up to 20 repeats. The lifetime of filaggrin is the time required for keratinocytes in the granular layer to move into the inner cornified layer. During this transition, filaggrin facilitates the collapse of corneocytes into ‘building blocks’ that become an impermeable surface barrier. The subsequent degradation of filaggrin is as remarkable as its synthesis, and the end-products aid in maintaining moisture in the cornified layer. It was apparent that ichthyosis vulgaris and atopic dermatitis were associated with the absence of this protein. McLean’s team in 2006 identified the cause of these diseases by discovering loss-of-function mutations in the profilaggrin gene, which led to dysfunction of the surface barrier. This story illustrates the complexity in maintaining a healthy, functional epidermis.
... 28 The irradiated skin at elevated levels also had increased levels of transglutaminase, which is a hallmark of compromised skin barrier as previously demonstrated in a SLS-challenged skin model. 29 The functional implications to the changes to transglutaminase has also been illustrated in patients suffering from atopic dermatitis (AD) and psoriasis, where lesional tissues marked increase in both TGM1 and TGM3. 5,6 The observed similarities in skin barrier changes following UV exposure with patients suffering from skin disorders further illustrates the importance of adequate photoprotection to prevent the alteration of barrier structure after receiving extended sunlight exposure. ...
Article
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The epidermal stratum corneum (SC) lipid matrix, principally consisting of an equimolar ratio of ceramides, free fatty acids, and cholesterol, plays a crucial role in maintaining proper skin barrier function. Conditions which impair barrier integrity, such as in atopic dermatitis, correlate with the alternation of key ceramide subclasses and reduced chain length of acyl moieties. However, there is limited knowledge about the impact of unprotected repeat sun exposure on the skin lipid composition, especially ceramide profiles.This study investigated the effects of ultraviolet (UV) radiation on the ceramide profile using both an ex vivo skin and a clinical model. Lipidomic analysis of UV-exposed skin showed shifts to the composition of ceramide subclasses essential in repairing and strengthening the SC barrier (including CER1[EOS], CER3[NP], and CER6[AP]) and reduced very long-chain acyl moieties. Gene expression analysis and immunohistochemical staining of key enzymes (aSMase, DES1, CerS5, CerS3) suggested that lipid alterations can be attributed to changes within the ceramide biosynthesis process. Topical application of ceramide-containing suncare products help maintain SC-essential ceramide subclasses and proper ceramide chain length, demonstrating the importance of proper photoprotection to maintain healthy skin barrier and ceramide quality during daily sun exposure. J Drugs Dermatol. 2022;21(1):77-85. doi:10.36849/JDD.6331.
... However, when KLK7 activity is too high, severe flaking of the skin and impaired barrier function can be triggered. Studies have shown that KLK7 levels are significantly increased in the stratum corneum of irritated [26] or inflamed [27] skin and that topical application of targeted active agents such as salicylic acid [10] can downregulate KLK7 expression and thus alleviate skin barrier damage. In this study, S1, S4, S6, and S9 inhibited KLK7 expression at high concentrations, while the study samples at low concentrations promoted KLK7 expression, indicating that the effective concentration of the active substance should be appropriately increased if the purpose of the cosmetic agent is to maintain the skin barrier. ...
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Background Sensitive skin is the result of a complex process that is closely linked to the damage of the skin barrier. There are no recognized methods for evaluating the efficacy of anti-allergy products. Methods In this study, a model of skin barrier damage was created by treating HaCaT cells with 60 μg/ml of sodium dodecyl sulfate for 48 h. The protective effects of nine cosmetic ingredients, including oat extract (S1), on the skin barrier were investigated based on the gene expression levels of aquaporin3 (AQP3), filaggrin (FLG), caspase-14 (CASP14), and human tissue kallikrein7 (KLK7), as well as those of various interleukins (IL) and vascular endothelial growth factor (VEGF). Results Among the nine ingredients, S1 had a good protective effect on the function of the skin barrier. It promoted the expression of AQP3, FLG, and CASP14, while inhibiting the expression of KLK7 in HaCaT cells, at a concentration of 0.06%. It also maintained IL-6, IL-8, and VEGF at appropriate levels while promoting the proliferation and differentiation of HaCaT cells. Conclusions The above indicators allow for the preliminary establishment of a method to evaluate the efficacy of the barrier protection ability of sensitive skin.
... Hard water increases epidermal deposition of sodium lauryl sulphate (SLS); a detergent commonly present in commercially available washing products [44]. It is thought that SLS deposition decreases profilaggrin expression, with subsequent reduction in NMF and up-regulation of protease activity [45,46]. An interventional study is ongoing in the UK, aimed at examining whether installation of a water softener before birth is able to prevent skin barrier breakdown and AD development [47]. ...
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Purpose of review Atopic dermatitis (AD) is a chronic inflammatory skin disorder affecting up to 20% of children and up to 5% of adults worldwide, contributing to significant disease-related morbidity in this patient cohort. Its aetiopathogenesis is underpinned by multiple factors, including genetic susceptibility, skin barrier defects, a skewed cutaneous immune response and microbiome perturbation in both the skin and the gut. In this review, we aim to examine the biological effects of key environmental exposures (the sum of which is termed the “exposome”) at the population, community and individual levels in order to describe their effect on AD pathogenesis. Recent findings It is now understood that as well as considering the type of environmental exposure with regard to its effect on AD pathogenesis, the dosage and timing of the exposure are both critical domains that may lead to either exacerbation or amelioration of disease. In this review, we consider the effects of population-wide exposures such as climate change, migration and urbanization; community-specific exposures such as air pollution, water hardness and allergic sensitisation; and individual factors such as diet, microbiome alteration, psychosocial stress and the impact of topical and systemic therapy. Summary This review summarises the interaction of the above environmental factors with the other domains of AD pathogenesis, namely, the inherent genetic defects, the skin barrier, the immune system and the cutaneous and gut microbiota. We specifically emphasise the timing and dosage of exposures and its effect on the cellular and molecular pathways implicated in AD.
... After years of intensive use in pharmaceutical technology, there have been increasing numbers of scientific investigations reporting negative effects on skin physiology. Treatment of the skin with SDS has been shown to increase transepidermal water loss (TEWL) [12][13][14] and to affect keratinocyte differentiation and desquamation [15,16]. SDS not only affects SC integrity, but also acts on deeper skin layers, where it is able to trigger skin irritations and allergies [11,17,18]. ...
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1) Background: The aim of the study was to evaluate the effect of pure lecithins in comparison to a conventional surfactant on skin in vivo. (2) Methods: Physiological skin parameters were evaluated at the beginning and the end of the study (day 1 and day 4) (n = 8, healthy forearm skin) with an Aquaflux ® , skin-pH-Meter, Corneometer ® and an Epsilon ® sensor. Confocal Raman spectroscopy was employed to monitor natural moisturizing factor, urea and water content of the participants' skin. Tape strips of treated skin sites were taken and the collected corneocytes were subjected to atomic force microscopy. Circular nano objects were counted, and dermal texture indices were determined. (3) Results: Transepidermal water loss was increased, and skin hydration was decreased after treatment with SDS and LPC80. Natural moisturizing factor and urea concentrations within the outermost 10 µm of the stratum corneum were lower than after treatment with S75 or water. Dermal texture indices of skin treated with SDS were higher than skin treated with water (control). (4) Conclusions: Results suggest very good (S75) or good (LPC80) skin-tolerability of lec-ithin-based surfactants in comparison to SDS and encourage further investigation.
... IL1, interleukin-1; TNFα, tumor necrosis factor α; PPARD, peroxisome proliferator-activated receptor β/δ; PPARG, peroxisome proliferator-activated receptor γ instigate irritant contact dermatitis in human skin. 19,[33][34][35][36] Acetone, an organic solvent, has commonly been used to perturb the cutaneous barrier in mice. 29,[37][38][39] Both compounds impair barrier function by removal and/or disturbance of SC intercellular lipid domains that are essential to maintain the epidermal permeability barrier. ...
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Peroxisome proliferator‐activated receptors (PPARs) are a family of nuclear hormone receptors. In skin, PPARs modulate inflammation, lipid synthesis, keratinocyte differentiation and proliferation and thus are important for skin barrier homeostasis. Accordingly, PPAR expression is altered in various skin conditions that entail epidermal barrier impairment i.e. atopic dermatitis (AD) and psoriasis. Using human epidermal equivalents (HEEs) we established models of acute epidermal barrier impairment devoid of immune cells. We assessed PPAR and cytokine expression after barrier perturbation and examined effects of keratinocyte‐derived cytokines on PPAR expression. We show that acetone or SDS treatment causes graded impairment of epidermal barrier function. Furthermore, we demonstrate that besides IL‐1β and TNFα, IL‐33 and TSLP are highly relevant markers for acute epidermal barrier impairment. Both SDS‐ and acetone‐mediated epidermal barrier impairment reduce PPARG expression levels, whereas only SDS enhances PPARD expression. In line with findings in IL‐1β and TNFα treated HEEs, abrogation of IL‐1 signaling restores PPARG expression and limits the increase of PPARD expression in SDS‐induced epidermal barrier impairment. Thus, following epidermal barrier perturbation, keratinocyte‐derived IL‐1β and partly TNFα modulate PPARG and PPARD expression. These results emphasize a role for PPARγ and PPARβ/δ in acute epidermal barrier impairment with possible implications for diseases such as AD and psoriasis.
... SLS is a surfactant used as a cleansing agent in common skincare products [11,12] and skin contact with detergent like SLS occurs on a daily basis. SLS as well as other synthetic surfactant can disturb skin lipids composition, remove lipids from stratum corneum surface and thereby disrupt the skin barrier function [24,25]. We have confirmed in this study, as already shown by other authors [26,27], that SLS applied as a patch induced skin barrier dysfunction by increasing TEWL and thus subsequently decreasing natural moisturizing factor, NMF, in skin moisturization: TEWL increase was significantly higher one day after SLS patch removal whereas skin moisturization was decreased. ...
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In this study, we assessed the change in skin microbiota composition, relative abundance, and diversity with skin physiology disruption induced by SLS patch. Healthy women declaring to have a reactive skin were submitted to a 0.5% aqueous sodium lauryl sulfate solution application under occlusive patch condition for 24 h. Skin properties were characterized by tewametry, corneometry, and colorimetry and bacterial diversity was assessed by 16S rRNA sequencing. Analysis before and one day after SLS patch removal revealed an increase of skin redness and a decrease of stratum corneum hydration and skin barrier function. The relative abundance of taxa containing potential pathogens increase (Firmicutes: Staphylococcaceae; Proteobacteria: Enterobacteriaceae, Pantoea) while some of the most occurring Actinobacteria with valuable skin protection and repair capacities decreased (Micrococcus, Kocuria, and Corynebacterium). We observed an impaired skin barrier function and dehydration induced by SLS patch disturb the subtle balance of skin microbiota towards skin bacterial community dysbiosis. This study provides new insights on the skin bacterial composition and skin physiology simultaneously impaired by a SLS patch.
... Exposure of SDS to mammals results in physical and biochemical effects: skin irritation, hyperplasia, alteration of serum lipid composition, damage of cells, and decrease in cell proliferation (Lindberg et al. 1992;Miura et al. 1989;van de Sandt et al. 1995). In amounts of 2 to 5%, SDS can cause sensitizing reactions, increase the transepidermal water loss of the stratum corneum, and result in mild skin inflammation affecting keratinocytes (Törmä et al. 2008;Dahl and Trancik 1977). ...
Article
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Background Using human keratinocyte HaCaT cell line model, we screened for proteins that changed their content due to SDS exposure in non-toxic dose (25 μg/ml, as determined by the MTT assay and microscopic examination) during 48 h. Methods The altered level of proteins from HaCaT keratinocytes exposed to SDS was analyzed by LC-MS/MS approach and quantified using Progenesis LC software. Results The Pathview map of 131 upregulated proteins was built, and enhancement of glycolysis/gluconeogenesis was found. Conclusions The results of our study admit the possibility of promotion of the cutaneous neoplasia and/or the peculiarity of the response of immortalized keratinocytes to the SDS treatment and provide new insights into possible role of SDS as integrator of diverse signaling that influence cell fate decisions.
... 109 It is believed sodium lauryl sulfate does this by inhibiting the expression of profilaggrin. 110 The water gradient in the SC controls filaggrin breakdown. 95 Filaggrin expression was decreased by 50% after 24 hours of occluded water exposure. ...
Article
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Objective: To provide an overview of filaggrin biology and the role of filaggrin variants in atopic dermatitis (AD) and allergic disease. Data sources: We performed a PubMed literature review consisting mainly of studies relating to filaggrin in the last 5 years. Study selections: We selected articles that were found in PubMed using the search terms filaggrin, atopic dermatitis, skin barrier, and atopy. Results: Filaggrin plays an important role in the development of AD and allergic disease. Novel methods in measuring filaggrin expression and identifying filaggrin mutations aid in stratifying this patient cohort. We review new insights into understanding the role of filaggrin in AD and allergic disease. Conclusion: Filaggrin remains a very important player in the pathogenesis of atopic dermatitis and allergic disease. This review looks at recent studies that aid our understanding of this crucial epidermal protein.
... 8,9 Patients with AD and even with atopic diathesis display skin barrier disruptions, which resemble the effects of sodium lauryl sulfate (SLS) exposure in higher concentrations. 10 SLS is a detergent commonly used in cosmetics, toothpastes and soaps due to its cleansing properties as an anionic surfactant. In dermatological research, SLS has been widely used to study irritant contact dermatitis. ...
Article
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Background: Sodium lauryl sulfate (SLS) is the best-studied detergent in irritant contact dermatitis. In atopic dermatitis, the two major pathophysiological abnormalities concern skin barrier function and regulation of cutaneous immune responses. The probability of atopic skin diathesis can be assessed by comprehensive analysis of patient history as well as clinical and laboratory findings resulting in the Erlangen Atopy Score (EAS). Objective: To investigate the impact of (i) atopic skin diathesis according to the EAS, and (ii) the physician-assessed diagnoses "atopic dermatitis", "allergic rhinitis", and "allergic asthma" on SLS skin reactions. Patients and methods: Retrospective analysis of data from 2,030 consecutive patients patch-tested with SLS (0.25% aq.) from two tertiary referral centers in Germany, from 2008 to 2014. Results: Patients with a high probability of atopic skin diathesis showed no significant increase in positive SLS reactions compared to patients without atopic skin diathesis (14.2 vs. 16.8%). The grading of positive SLS skin reactions (1-4) revealed no differences in patients with or without atopic skin diathesis. Further, diagnoses of atopic dermatitis, allergic rhinitis, or allergic asthma had no impact on positive SLS skin reactions in multivariate logistic regression analysis. Conclusions: We found no association of increased skin irritability to SLS with atopic skin diathesis, atopic dermatitis, allergic rhinitis, or allergic asthma in a large patient cohort. It therefore seems that the test of skin irritability with SLS, which is common practice in many centers so far, does not allow to predict the susceptibility to irritant eczematous inflammation in atopic vs. non-atopic individuals.
... We could also observe that the stratum corneum of Keraskin TM was severely damaged by SLS. In addition, it is known that SLS alters the expression pattern of keratinocyte differentiation markers [25]. We demonstrated that LR treatment causes the increased expression of skin barrier proteins at both protein and mRNA levels. ...
Article
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The main function of the skin is to protect the body from the external environment. The barrier function of the skin is mainly provided by the stratum corneum, which consists of corneocytes bound with the corneodesmosomes and lamellar lipids. Skin barrier proteins like loricrin and filaggrin also contribute to the skin barrier function. In various skin diseases, skin barrier dysfunction is a common symptom, and skin irritants like detergents or surfactants could also perturb skin barrier function. Many efforts have been made to develop strategies to improve skin barrier function. Here, we investigated whether the microfluidized lysates of Lactobacillus rhamnosus (LR), one of the most widely used probiotic species for various health benefits, may improve the skin barrier function in a reconstructed human epidermis, Keraskin™. Application of LR lysate on Keraskin™ increased the expression of tight junction proteins; claudin 1 and occludin as determined by immunofluorescence analysis, and skin barrier proteins; loricrin and filaggrin as determined by immunohistochemistry and immunofluorescence analysis and qPCR. Also, the cytotoxicity of a skin irritant, sodium lauryl sulfate (SLS), was alleviated by the pretreatment of LR lysate. The skin barrier protective effects of LR lysate could be further demonstrated by the attenuation of SLS-enhanced dye-penetration. LR lysate also attenuated the destruction of desmosomes after SLS treatment. Collectively, we demonstrated that LR lysate has protective effects on the skin barrier, which could expand the utility of probiotics to skin-moisturization ingredients.
... EU is reported to be the most promising enhancer for polar and water-soluble drugs among the terpenes [29], and is favoured for its relatively low toxicity and irritancy [30]. SLS is an anionic surfactant that is commonly used in personal care products and topical creams but may cause irritation and damage to the skin barrier [31]. It has been shown to interact with skin lipids and keratin and to affect epidermal differentiation and desquamation [32]. ...
Article
Background/aims: The mechanisms by which permeation enhancers increase human skin permeation of caffeine and naproxen were assessed in vitro. Methods: Active compound solubility in the vehicles and in the stratum corneum (SC), active compound flux across epidermal membranes and uptake of active and vehicle components into the SC were measured. The effect of vehicle pH on the permeation of caffeine and naproxen was also determined. Results: Oleic acid and eucalyptol significantly enhanced the skin penetration of caffeine and naproxen, compared to aqueous controls. Naproxen permeation was increased from vehicles with pH presenting more ionized naproxen. Caffeine maximum flux enhancement was associated with an increase in caffeine SC solubility and skin diffusivity, whereas for naproxen a penetration enhancer/vehicle-induced increase in solubility in the SC correlated with an increase in maximum flux. SC solubility was related to experimentally determined active uptake, which was in turn predicted by vehicle uptake and active compound solubility in the vehicle. Conclusion: A permeation enhancer-induced alteration in diffusivity, rather than effects on SC solubility, was the main driving force behind increases in permeation flux of the hydrophilic molecule caffeine. For the more the lipophilic molecule naproxen, increased SC solubility drove the increases in permeation flux.
... On the other hand, the detergent sodium lauryl sulfate (SLS) is a common test substance for induction of skin barrier damage. The time and quality of the barrier repair after the damage with this chemical is often used as an indicator of how well various treatments affect the healing of skin (Kartono and Maibach, 2006;Törmä et al., 2008). Regarding the importance of all phases in the complex process of wound healing, the in vivo assesment of damaged skin barrier repair could be a useful additional tool to scratch assay. ...
Article
Ethnopharmacological relevance: Alchemilla vulgaris is an important remedy in European folk medicine, known for its astringent and anti-inflammatory properties; it is traditionally used to heal gynecological and gastrointestinal diseases. Despite its folkloric use in wound healing, there is a lack of scientific data to support this therapeutic application. Aim of the study: To analyze the wound healing potential of different solvent A. vulgaris extracts per se and after incorporation into hydrogels as topical vehicles, using two complementary methods - in vitro wound healing assay with L929 fibroblasts and in vivo assessment of skin barrier repair potential. Besides scientific justification of the traditional usage, we aimed to ephasize the importance of a proper vehicle for herbal extracts. The wound healing activity has been connected to the chemical profile of the investigated extracts, their antioxidative properties, but also to pH of the investigated gels and their mechanical characteristics. Materials and methods: Antioxidant activity of investigated extracts was estimated using both 2,2-diphenyl-1-picrylhydrazyl and β-carotene/linoleic acid models. Chemical profile was achieved applying spectrophotometric and HPLC methods. In vitro scratch assay with L929 fibroblasts, and in vivo study of skin barrier repair potential of hydrogels with A. vulgaris extracts on human skin employing biophysical measurements, were performed in order to confirm the wound healing potential of A. vulgaris. Texture analysis of the gels was performed alongside the pH measurements. Results: All tested extracts and gels accelerated the wound healing process while the effect of ethanolic extract on migration of fibroblasts was the most pronounced. The highest extent of wound closure was also observed for the ethanolic extract. The most favorable effect on in vitro wound healing was observed for gel with propyleneglycolic extract. Results of in vivo study were in line with in vitro findings. Healing potential may be attributed to phenolic compounds found in A. vulgaris extracts, low pH of the gels, and the satisfying antioxidant activity of the extracts. Parameters obtained by textural analysis indicated satisfying mechanical properties of the gels, relevant to topical application. Conclusion: Our study offers pharmacological evidence on the folkloric use of A. vulgaris in wound treatment, particularly after incorporation into hydrogel, and underlines an importance of a proper vehicle for incorporation of herbal extracts intended for topical treatment.
... Interestingly, NMF levels in both groups significantly decreased at follow-up compared to baseline. Exposure to water and soap has been shown to reduce NMF levels by different mechanisms (32)(33)(34)(35), however this cannot explain decrease in NMF as wet work exposure did not change during the trial. One of the possible explanations might be introduction of a new disinfectant containing n-propanol instead of the formerly used ethanol, shortly before the start of our trial. ...
Article
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Background Healthcare workers (HCW) are at risk for developing hand dermatitis (HD). Guidelines recommend moisturizers to prevent HD, but in practice their effectiveness is poorly investigated. Objectives To assess whether an intervention aimed at improving skin care leads to reduction in HD severity. Methods In this 1‐year RCT, 9 wards (285 HCW) were allocated to an intervention group (IG) and 10 wards (216 HCW) to the control group (CG). The intervention included provision of cream dispensers with electronic monitoring of use, regularly communicated to the HCW. The primary and secondary outcomes were change from baseline in Hand Eczema Severity Index (∆HECSI) and Natural Moisturizing Factor (∆NMF) levels. Results At 12 months, lost‐to‐follow‐up was 41% and 39% in the IG and CG, respectively. The HECSI was reduced in the IG by ‐6.2 (95%CI ‐7.7,‐4.7) and in the CG by ‐4.2 points (95%CI ‐6.0,‐2.4). There was no difference in ∆HECSI or ∆NMF between groups. Relative improvement in HECSI was significantly higher in the IG than in CG (56% vs. 44%). In a subgroup of HCW with mild HD, IG showed larger HECSI decrease than CG (P<0.001) Conclusion Although there was no significant effect on the primary outcomes, the intervention showed overall positive effects on HECSI. This article is protected by copyright. All rights reserved.
... 8,9,11 Reduced amount of filaggrin in the skin can be either congenital or due to exogenous factors. [44][45][46] Previous studies have shown NMF to be affected by allergens and irritants, 47 as well as atopic dermatitis. 48,49 If the expression of filaggrin was affected due to tattooing, we would expect the tattooed skin area to contain a lower level of NMF than the corresponding non-tattooed skin. ...
Article
Background Initially after tattooing, the skin barrier function is broken. However, the long‐term impact of clinically healed tattoos on this has never been studied. The aim was to investigate the long‐term effect on the skin barrier function in normal tattoos and examples of tattoos with chronic inflammatory complication. Methods Participants were recruited from the “Tattoo clinic” of the Dermatological Department on Bispebjerg Hospital in Denmark, where patients with complicated tattoo reactions are treated. Transepidermal water loss (TEWL), conductance, capacitance, and pH were measured in tattooed skin with regional control measurements in normal non‐tattooed skin. Natural moisturizing factor (NMF) was measured in collected tape strips. Results Twenty six individuals with 28 tattoos were included, that is, 23 normal tattoos without any pathologic reaction and 5 tattoos with chronic inflammatory complications. No significant differences were found in tattooed versus non‐tattooed skin with respect to TEWL (median values 6.6 vs 7.2 g/m²/h), conductance (76 vs 78 a.u.), pH (5.94 vs 5.79), and NMF (0.58 vs 0.59 mmol/g protein). Capacitance (64 vs 57 a.u.) was higher in tattooed skin compared to non‐tattooed skin (P = 0.006). Similar results were found in tattoos with inflammatory reactions. Conclusion Overall, skin tattoos do not affect the long‐term skin barrier function markedly. The skin capacitance was, however, affected in tattooed skin areas compared to non‐tattooed skin areas.
... Thus, water downregulated FLG expression by 50% after 24 h of occluded exposure. 33 So-called hard water appears to have the most negative effect on the skin barrier, which, in turn, may increase the risk of AD. 34 Accordingly, a higher prevalence of AD in children residing in regions with hard domestic water has been found. 16,18,35,36 A high calcium carbonate content is normally associated with an elevated pH, which may result in premature activation of serine proteases that, in turn, degrade corneodesmosomes. ...
Article
Atopic Dermatitis (AD) is a common type of eczema. There is often a greater risk of getting AD by having a deficiency of NMFs (natural moisturising factors) that come from filaggrin in the skin. Filaggrin is a protein in your skin that plays a vital role in the skin barrier function and in releasing acids that help in water retention. While it is now known that AD is caused by the gene mutation of filaggrin, there has been little research done into environmental factors that can cause a deficiency of filaggrin in the body. A Danish study funded by the Lundbeck Foundation has attempted to discover what types of environmental skin stressors can impact on levels of NMF and cytokines. Cytokines are cell molecules that stimulate the movement of cells towards inflammation, infection and trauma. In the study, 40 healthy volunteers (18‐49) were exposed to hard, soft and chlorinated water, Sodium Lauryl Sulfate (SLS – a chemical found in foaming products such as shampoo), house mite dust, cat allergen, Staphylococcal enterotoxin B (SEB ‐ a protein commonly associated with food poisoning), cooling and histamine (a chemical created by the immune system). The volunteers were tape stripped (this means applying tape to the skin and then removing it and looking at the tape under a microscope) and the biological changes recorded after 24 and 48 hours for NMFs and after 24 hours for cytokines. At 24 hours, a significant decrease of NMFs was recorded for hard and soft waters, house dust mites and SEBs with an increase in cytokines compared with control tests. The study concluded that exposure to skin stressors causes NMF levels to decrease, with an additional increase in various types of cytokines, in healthy people. This data highlights that environmental data might play a role in AD pathophysiology.
... Benzophenone is associated with cellular damage, endocrine disruption, organ system toxicity and cancer [28]. Sodium Laureth (or Lauryl) Sulfate which is added as to shampoos, soaps, toothpastes and body wash etc. as foaming agent is also a matter of concern as it might get contaminated with a carcinogen 1, 4 dioxane (used for sterilization of the product) during the manufacturing process [29]. ...
Article
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Baby cosmetics and personal care range of products is an essential part of daily needs of all the infants now days. These products are available in a wide variety to fulfil all the skin care and hygienic requirements of the young ones. However, it should be kept in mind that the chemicals used as additives in these products might be harmful to the immature skin and immunity of an infant. This article presents a review of the possible contaminants and intentionally added additives which are known to cause harm to human system. Our intention is to spread awareness among scientific community as well as the end users i.e. the parents of infants about these chemicals so that they can judge these products for their safety and quality on their own.
... Some TJ-related proteins were decreased after laser applications to the psoriasis-and ADlike skin. Acute barrier perturbation can reportedly lower the mRNA levels of profilaggrin and involucrin (48). With respect to the psoriasis-like skin, peptide permeation was significantly increased by the Er:YAG laser but not by the Er:glass laser. ...
Article
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Purpose: Most of the investigations into laser-assisted skin permeation have used the intact skin as the permeation barrier. Whether the laser is effective in improving cutaneous delivery via barrier-defective skin is still unclear. Methods: In this study, ablative (Er:YAG) and non-ablative (Er:glass) lasers were examined for the penetration of peptide and siRNA upon topical application on in vitro skin with a healthy or disrupted barrier. Results: An enhanced peptide flux (6.9 fold) was detected after tape stripping of the pig stratum corneum (SC). A further increase of flux to 11.7 fold was obtained after Er:YAG laser irradiation of the SC-stripped skin. However, the application of Er:glass modality did not further raise the flux via the SC-stripped skin. A similar trend was observed in the case of psoriasiform skin. Conversely, the flux was enhanced 3.7 and 2.6 fold after treatment with the Er:YAG and the Er:glass laser on the atopic dermatitis (AD)-like skin. The 3-D skin structure captured by confocal microscopy proved the distribution of peptide and siRNA through the microchannels and into the surrounding tissue. Conclusions: The fractional laser was valid for ameliorating macromolecule permeation into barrier-disrupted skin although the enhancement level was lower than that of normal skin.
... The structural components of the stratum corneum, such as the extracellular lipid matrix, the cornified envelope, and the corneodesmosomes, are primary targets for most irritants (13). Recently, it has been shown that the model irritant sodium lauryl sulfate (SLS) affects the expression of filaggrin (14,15). Similar morphological changes have also been seen in mice when they are exposed to 2,4,6-trinitro-1-chlorobenzene, a potent contact allergen (16). ...
Article
BACKGROUND: The irritant sodium lauryl sulfate (SLS) is known to cause a decrease in the stratum corneum level of natural moisturizing factor (NMF), which in itself is associated with changes in corneocyte surface topography. OBJECTIVE: To explore this phenomenon in allergic contact dermatitis. METHODS: Patch testing was performed on patients with previously positive patch test reactions to potassium dichromate (Cr), nickel sulfate (Ni), methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), or p-phenylenediamine. Moreover, a control (pet.) patch and an irritant (SLS) patch were applied. After 3 days, the stratum corneum from tested sites was collected, and NMF levels and corneocyte morphology, expressed as the amount of circular nanosize objects, quantified according to the Dermal Texture Index (DTI), were determined. RESULTS: Among allergens, only MCI/MI reduced NMF levels significantly, as did SLS. Furthermore, only MCI/MI caused remarkable changes at the microscopic level; the corneocytes were hexagonal-shaped with pronounced cell borders and a smoother surface. The DTI was increased after SLS exposure but not after allergen exposure. CONCLUSIONS: MCI/MI significantly decreased NMF levels, similarly to SLS. The altered corneocyte morphology suggests that skin barrier damage plays a role in the pathogenesis of MCI/MI contact allergy. The DTI seems to differentiate reactions to SLS from those to the allergens tested, as SLS was the only agent that caused a DTI increase.
... Thus, water downregulated FLG expression by 50% after 24 h of occluded exposure. 33 So-called hard water appears to have the most negative effect on the skin barrier, which, in turn, may increase the risk of AD. 34 Accordingly, a higher prevalence of AD in children residing in regions with hard domestic water has been found. 16,18,35,36 A high calcium carbonate content is normally associated with an elevated pH, which may result in Data are presented as boxplots with Tukey-style whiskers. ...
Article
Background: Epidermal deficiency of filaggrin, and the derived natural moisturizing factors (NMF), is associated with increased risk of atopic dermatitis (AD). While filaggrin gene mutations cause filaggrin deficiency, there is limited insight in causative environmental factors. Objective: To explore the effect of selected exogenous skin stressors on NMF and skin cytokines levels in healthy adult epidermis. Material and methods: 40 healthy volunteers (18-49 years) were exposed to hard, soft, and chlorinated water, 0.5% SLS, house dust mite, cat allergen, staphylococcal enterotoxin B (SEB), cooling and histamine. Participants were tape-stripped and biophysiological measurements were performed. NMF was determined after 24 and 48 hours, while skin cytokines were measured after 24 hours for selected exposures. Results: At 24 hours, a significant decrease in NMF was observed for soft (0.51±0.19) and hard water (0.61±0.32) compared to occlusion alone (0.71±0.18). Hard water led to increased levels of IL-4, IFN-ɣ and IL-10. Exposure to house dust mite and SEB led to a significant decrease in NMF after 24 hours (0.77 ±0.28 and 0.80±0.28, respectively) compared to occlusion alone (1.00±0.42). House dust mite led to an increase in IFN-ɣ, IL-2 and IL-4, as compared to the non-occluded control site. Conclusion: Based on experimental exposure to selected atopic skin stressors such as different water types, allergens and SEB, we conclude that NMF levels are decreased along with increased secretion of various skin cytokines in healthy individuals. Our data highlight environmental factors that might play a role in AD pathophysiology, but needs confirmation in AD patients. This article is protected by copyright. All rights reserved.
... An FLG-deficient mouse model showed spontaneous dermatitis with impaired skin barrier and delayed skin barrier recovery from irritation [25,29]. Moreover, external stimuli increased FLG and IVL expressions in the healthy skin of a human and mouse model; the authors indicated that such an outcome is a comprehensive effect of the skin normalizing the skin barrier [30,31]. ...
Article
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Radiation-induced skin injury can take the form of serious cutaneous damage and have specific characteristics. Asymptomatic periods are classified as the latent stage. The skin barrier plays a critical role in the modulation of skin permeability and hydration and protects the body against a harsh external environment. However, an analysis on skin barrier dysfunction against radiation exposure in the latent stage has not been conducted. Thus, we investigated whether the skin barrier is impaired by irradiation in the latent stage and aimed to identify the molecules involved in skin barrier dysfunction. We analyzed skin barrier function and its components in SKH1 mice that received 20 and 40 Gy local irradiation. Increased transepidermal water loss and skin pH were observed in the latent stage of the irradiated skin. Skin barrier components, such as structural proteins and lipid synthesis enzymes in keratinocyte, increased in the irradiated group. Interestingly, we noted sebaceous gland atrophy and increased serine protease and inflammatory cytokines in the irradiated skin during the latent period. This finding indicates that the main factor of skin barrier dysfunction in the latent stage of radiation-induced skin injury is sebaceous gland deficiency, which could be an intervention target for skin barrier impairment.
... Of these, TGase1 catalyzes the formation of ε-(γ-glutamyl) lysine cross-links, and is closely involved in the formation of robust CEs, which facilitate the barrier functions of the stratum corneum [5,22]. In rough skin with a compromised barrier function, ε-(γ-glutamyl) lysine cross-linking induced by TGase is insufficient, precluding the formation of robust CEs and reducing the levels of intercorneocyte ceramides [9,10,23]. TGase1 is an enzyme that strengthens the barrier function of the stratum corneum and participates in the formation of strong CEs [5]. Therefore, it is an important enzyme for normal stratum corneum formation. ...
Article
Full-text available
We investigated whether 3-(trihydroxygermyl) propionic acid increases the formation of cornified cell envelopes and the level of ceramide in cultured epidermal keratinocytes and in a three-dimensional human epidermis model. The activity and mRNA expression of transglutaminase were increased when 3-(trihydroxygermyl) propionic acid was added to the cell cultures. The formation of cornified cell envelopes in cultured human epidermal keratinocytes was increased in the presence of 3-(trihydroxygermyl) propionic acid. Ceramide levels were increased in the presence of 3-(trihydroxygermyl) propionic acid. The activity of serine palmitoyltransferase and mRNA levels of serine palmitoyltransferase 2 were also increased when 3-(trihydroxygermyl) propionic acid was added to the cultures. The extent to which ceramide levels were increased in the presence of 3-(trihydroxygermyl) propionic acid appeared dependent on serine palmitoyltransferase 2 upregulation. These results suggest that 3-(trihydroxygermyl) propionic acid can promote cornified cell envelope formation by inducing transglutaminase expression and ceramide synthesis via the induction of serine palmitoyltransferase activity, thereby improving the barrier function and moisture of dry, rough skin.
Article
Objective Basic therapy is an integral part of the treatment of chronic skin diseases. However, the formulation of skin products should be analysed with respect to the physical stability and tolerance by the patients before applying them to diseased skin. In particular, the suitability of the formulation for use on damaged skin should be taken into consideration so that no exacerbation of the condition is caused. Methods The following approach investigated two formulations with the emulsifier sorbitan monostearate and one with the addition of polyethylene glycol 100 stearyl ether. The characterization included rheology, macroscopic and microscopic cream analysis compared to marketed products for basic therapy. Pyranine staining of stratum corneum (SC) and trans‐epidermal water loss (TEWL) measurements were performed with ex vivo porcine SC to asses skin barrier function. Results The rheological characterization showed a gel‐like, viscoelastic behaviour of the formulations and a viscosity in the same order of magnitude as the marketed products. Staining with pyranine revealed that skin damage caused by sodium lauryl sulfate was compensated by treatment with the developed formulations. Following the same trend, TEWL results clearly showed decreasing values, which evidence improved skin barrier function. Conclusion In conclusion, the developed sorbitan monostearate formulations can potentially improve deficient skin barrier function as a part of basic therapy of skin diseases and act as a superior alternative to market products comprising a minimum of well‐chosen ingredients.
Chapter
The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell-mediated immune responses, IgE-mediated hypersensitivity, and environmental factors. Loss-of-function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified, which may alter the skin’s barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell-mediated immune responses and can promote IgE-mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin’s pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis, which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.
Chapter
The pathogenesis of atopic dermatitis (AD) involves multiple elements including cutaneous microbiome perturbation, disruption of the skin barrier, genetic susceptibility, and altered immune response. We review the role of environmental and dietary exposures in AD pathogenesis. We highlight the effects of environmental exposures on the molecular and cellular pathways involved in AD. Additionally, we present a patient that responded well to heliotherapy. Although diet has been known to be associated with AD, much remains unknown. Patients and clinicians may struggle to distinguish between exacerbations of AD and true food allergies (FA), secondary to specific dietary exposures. We discuss various adverse reactions to food and discuss current methods of investigation and diagnosis. Based on our current understanding, it appears that a compromised skin barrier and skin and gut microbiome dysbiosis are associated with both AD and FA. Lastly, the role of oral supplements and vitamins in the management of AD is discussed.
Article
Trans-epidermal water loss (TEWL) has been the most widely used method to assess the integrity of the skin barrier and evaluate the irritation potential or the protective properties of topical products for many years. It detects the amount of water that diffuses across the stratum corneum (SC) to the external environment. As one of the most important functions of the skin is to keep water inside the body, an increase in TEWL is used to indicate the skin's impaired barrier function. So far, a variety of commercial instruments are available to measure the TEWL. Their applications mainly focus on the in-vivo TEWL measurements for dermatological examinations or formulation development. Recently, an in-vitro TEWL probe has also been commercially released enabling preliminary tests with excised skin samples. In our study, we first aimed to optimize the experimental procedures for detecting the in-vitro TEWL of porcine skin. Secondly, different kinds of emulsifiers were applied to the skin, including polyethylene glycol-containing emulsifiers (PEG-ylated emulsifiers), sorbitan esters, cholesterol, and lecithin. Sodium lauryl sulfate (SLS) was used as a positive control, and water as a negative control. Based on the findings, we established a protocol for accurately measuring the in-vitro TEWL values, emphasizing that the temperature of the skin sample should be constantly maintained at 32℃. Subsequently, the influences of emulsifiers on the in-vitro TEWL were analyzed. They indicated a significant skin barrier impairment of PEG-20 cetyl ether, PEG-20 stearyl ether, and SLS on in-vitro skin. Furthermore, we interestingly found that there consistently was an alteration of the TEWL values, even after the application of water to the skin. Our findings are of special interest, as the European Medicines Agency (EMA) recommends the use of in-vitro TEWL to determine skin barrier intactness during Franz cell experiments. Thus, this study provides a validated protocol for measuring the in-vitro TEWL and elucidates the impact of emulsifiers on the skin barrier. It also improves the understanding of tolerable variations of in-vitro TEWL and offers recommendations for its use in research.
Article
Food allergy is often associated with development of atopic dermatitis. Atopic dermatitis is a chronic inflammatory skin condition with a strong association with skin barrier gene mutations. Loss-of-function mutations in skin barrier genes increase transepidermal water loss. Also, reduction of the skin barrier can be mediated by environmental exposures. In preclinical studies of mice with skin barrier disruption, exposure to allergens on the skin induces food allergy. Exposure to food allergens on the skin with coexposure of the skin to other environmental factors induces signals in the skin for activation of food allergy, allergen-specific IgE, and oral food–induced anaphylaxis. In contrast, oral food allergen consumption before skin exposure to food allergen induces tolerance to the food allergen. However, this induction of tolerance may be blocked if skin is exposed to environmental allergens at the time of initial oral food allergen consumption. Further studies are needed to address the mechanisms of induction of food allergy by coexposure of the skin to food allergens, aeroallergens, and other environmental factors. Furthermore, clinical studies are needed to determine the effects of food allergen on skin before skin development of atopic dermatitis.
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Ammonium bituminosulfonate preparations have been used for various dermatological diseases since the 19th century. The dark preparation is known as the so-called “drawing salve” (Ichtholan®) for the treatment of abscesses and furuncles. The underlying activity is in part the loosening of the skin, which facilitates pus extraction and treatment of deep inflammations. For this investigation 3D skin models were incubated with ointments containing different ammonium bituminosulfonate concentrations. Histological and immunohistochemical staining as well as penetration investigation were carried out. The effect of dark ammonium bituminosulfonate ointments on skin loosening was investigated to reveal the underlying mechanism. The skin loosening effect could be proved by HE-staining for ammonium bituminosulfonate treated skin models. This effect was concentration dependent. While treatment with ammonium bituminosulfonate ointment had no influence on keratin expression, high concentrated ointments led to decreased filaggrin and laminin expression. Treatment of skin models with ABS ointments led to an increased skin permeability, which was concentration dependent. For the first time the skin loosening effect of ammonium bituminosulfonate ointment has been demonstrated on 3D skin models. This effect is at least in part caused by the interaction of the substance with structure dependent proteins of the epidermis.
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Background Food allergy is thought to develop through transcutaneous sensitization, especially in the presence of skin barrier impairment and inflammation. Regular moisturizer application to infant skin could potentially promote transcutaneous sensitization and the development of food allergy. Objectives We tested this hypothesis in the Enquiring About Tolerance (EAT) study population. Methods The EAT study was a population-based randomized clinical trial conducted from January 15, 2008, to August 31, 2015, and recruited 1303 exclusively breastfed 3-month-old infants and their families from England and Wales. At enrollment at 3 months, families completed a questionnaire that included questions about frequency and type of moisturizer applied, use of corticosteroid creams, and parental report of dry skin or eczema. Infants were examined for visible eczema at the enrollment visit. Results A statistically significant dose-response relationship was observed between parent-reported moisturization frequency at 3 months of age and the subsequent development of food allergy. Each additional moisturization per week was associated with an adjusted odds ratio of 1.20 (95% CI, 1.13-1.27; P < .0005) for developing food allergy. For infants with no visible eczema at the enrollment visit, the corresponding adjusted odds ratio was 1.18 (95% CI, 1.07-1.30; P = .001) and for those with eczema at the enrollment visit, 1.20 (95% CI, 1.11-1.31; P < .0005). Moisturizer frequency showed similar dose-response relationships with the development of both food and aeroallergen sensitization at 36 months. Conclusions These findings support the notion that regular application of moisturizers to the skin of young infants may promote the development of food allergy through transcutaneous sensitization.
Article
Background The skin barrier consists of multiple lipid-enriched layers, which are characterized by lamellar repeated structures within the intercellular space. Sodium lauryl sulfate is a well-known substance that can disrupt the skin barrier. The mechanisms underlying the barrier repair process, especially the influence of topical sodium lauryl sulfate treatment on lipid transport in the barrier recovery phase, remain unresolved. Objective To understand the process of reconstruction of the intercellular lipid layer of the skin after acute barrier disruption by sodium lauryl sulfate treatment in vivo. Methods Female hairless mice were treated with 3% sodium lauryl sulfate. Transepidermal water loss measurement, histopathological analysis, and gene expression analysis were performed from 1 to 288 h after the topical application of sodium lauryl sulfate. Western blot analysis, immunofluorescence staining, and transmission electron microscopy analysis were performed to examine the expression level of ATP-binding cassette, sub-family A, member 12 (ABCA12), and the secretion level of lamellar bodies. Results We observed rapid hyper-keratinization at the stratum corneum and the subsequent concurrent secretion of lamellar bodies into the intercellular space of the stratum corneum during the process of skin barrier recovery. ABCA12 expression associated with lipid transportation into lamellar bodies was transiently upregulated and observed in multiple layers in the upper epidermis, especially in the stratum granulosum. Conclusion The skin reacts appropriately to maintain its barrier function by first initiating hyper-keratinization and then increasing lamellar body secretion. Activation of ABCA12 is an essential factor for the recovery of skin barrier function.
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Senile xerosis is one of the most common pathology in elderly patients. The article presents an overview of current knowledge on the subject of skin barrier function and pathophysiological mechanisms and clinical features of senile xerosis. The corneotherapeutic approach to treatment of senile xerosis is substantiated and the effectiveness of emollients for baths was justified. The pH of water various sources (tap and artesian water) has alkaline values, which leads to an increase in dry skin and worsening clinical symptoms of xerosis. The effectiveness of bath emollients was investigated. The analysis of the adsorption properties of bath emollients was conducted which showed that these properties depend on pH of water. Hydrotherapy with using the citrate buffer system increases the efficiency of treatment. 60 women, aged 75-84 years, diagnosed with senile xerosis were treated with hydrotherapy containing citrate buffer system, bath emollient (shower oil). A clinical assessment was performed at the beginning and end of the study by a dermatologist using the Overall Dry Skin Scale (ODS) and Dermatological Life Quality Index (DLQI). Hydrotherapy with using a citrate buffer system provided a significant softening of the skin, elimination of scaling, remission of pruritus and more rapid clinical effect.
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The understanding of monogenetic disorders of cornification, including the group of diseases called ichthyoses, has expanded greatly in recent years. Studies of the aetiology of more than 50 types of ichthyosis have almost invariably uncovered errors in the biosynthesis of epidermal lipids or structural proteins essential for normal skin barrier function. The barrier abnormality per se may elicit epidermal inflammation, hyperproliferation and hyperkeratosis, potentially contributing to the patient's skin symptoms. Despite this and other new knowledge about pathomechanisms, treatment of ichthyosis often remains unsatisfactory. This review highlights a series of approaches used to elucidate the pathobiology and clinical consequences of different types of ichthyosis, and related diseases with the ultimate goal of finding new and better treatments.
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Atopic dermatitis (AD) is a complex inflammatory disorder with multiple interactions between genetic, immune and external factors. The sum of external factors that an individual is exposed to throughout their lifetime is termed the exposome. The exposome spans multiple domains from population to molecular levels and, in combination with genetic factors, holds the key to understanding the phenotypic diversity seen in AD patients. Exposomal domains are categorized into nonspecific (human and natural factors affecting populations), specific (eg humidity, ultraviolet radiation, diet, pollution, allergens, water hardness) and internal (cutaneous and gut microbiota and host cell interaction) exposures. The skin, as the organ that most directly interacts with and adapts to the external environment, is a prime target for exploration of exposomal influences on disease. Given the well‐recognized physical environmental influences on AD, this condition could be much better understood through insightful exposomal research. In this narrative review, we examine each domain in turn, highlighting current understanding of the mechanisms by which exposomal influences modulate AD pathogenesis at distinct points in time. We highlight current approaches to exposome modification in AD and other allergic disease and propose future directions for exposome characterization and modification using novel research techniques.
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Skin diseases represent one of the most common work‐related diseases and may have a detrimental effect on social, personal and occupational aspects of life. Contact dermatitis, which comprises predominately irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) accounts for vast majority of occupational skin diseases, especially in occupations associated with frequent skin contact with irritants and contact allergens. Although ICD and ACD have similar clinical manifestation, their pathophysiology and the role of the skin barrier is different. In ICD, perturbation of the skin barrier is the primary event which sets into motion diverse metabolic processes and triggers activation of innate immunity without involvement of adaptive immune system. In ACD, a type IV hypersensitivity reaction induced by contact allergens, the skin barrier impairment may evoke innate signaling pathways during the sensitization phase required for the activation of T‐cell adaptive response. Thus, skin barrier impairment may increase the risk of ICD or ACD not only because of enhanced permeability and ingress of irritants and allergens, but also by generation of innate immune signal needed for the induction of allergic response. Hence, an efficient way to prevent CD is to avoid skin barrier damage in the workplace. This review focuses on the skin barrier, how it is affected by skin irritants and how its impairment contributes to development of ICD and ACD. This article is protected by copyright. All rights reserved.
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The purpose of this study was to investigate the impact of emulsifiers and formulations on intercellular lipids of porcine stratum corneum (SC) and evaluate confocal Raman microscopy (CRM) as an alternative method in this research context. To this end, four different formulations were used: three conventional creams that contained ionic and/or non-ionic emulsifiers and one surfactants-free emulsion stabilized by a polymeric emulsifier. Additionally, all emulsifiers were tested in aqueous solution/dispersion in the respective concentrations as present in the formulations. CRM and HPTLC were used to analyse changes in SC lipid content after treatment. Furthermore, lipid extraction was visualized by fluorescence staining and SC thickness was measured by CRM and light microscopy. Various emulsifiers and emulsifier mixtures showed different impact on SC lipid content and SC thickness, while none of the tested formulations had any effect on SC lipids. Emulsifiers and their mixtures that reduced the lipids content also reduced SC thickness, indicating lipid extraction is the reason for SC thinning. Results from CRM and conventional methods showed a strong positive correlation for both lipid content and SC thickness measurements. With easy sample preparation and fast analytical readout, CRM has the potential to be a standardized analytical method for skin lipids investigation.
Chapter
The pathophysiology of atopic dermatitis is complex and multifactorial, involving elements of barrier dysfunction, alterations in cell mediated immune responses, IgE mediated hypersensitivity, and environmental factors. Loss of function mutations in filaggrin have been implicated in severe atopic dermatitis due to a potential increase in trans-epidermal water loss, pH alterations, and dehydration. Other genetic changes have also been identified which may alter the skin’s barrier function, resulting in an atopic dermatitis phenotype. The imbalance of Th2 to Th1 cytokines observed in atopic dermatitis can create alterations in the cell mediated immune responses and can promote IgE mediated hypersensitivity, both of which appear to play a role in the development of atopic dermatitis. One must additionally take into consideration the role of the environment on the causation of atopic dermatitis and the impact of chemicals such as airborne formaldehyde, harsh detergents, fragrances, and preservatives. Use of harsh alkaline detergents in skin care products may also unfavorably alter the skin’s pH causing downstream changes in enzyme activity and triggering inflammation. Environmental pollutants can trigger responses from both the innate and adaptive immune pathways. This chapter will discuss the multifaceted etiology of atopic dermatitis which will help us to elucidate potential therapeutic targets. We will also review existing treatment options and their interaction with the complex inflammatory and molecular triggers of atopic dermatitis.
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Oxidative stress is a universal response of the skin cell damage of various origins. Sodium dodecyl sulfate (SDS, sodium lauryl sulfate) is an anionic surfactant commonly used as an emulsifying detergent in household cleaners. Sodium dodecyl sulfate is the reference compound for testing toxicity on cellular skin models. The effect of sodium dodecyl sulfate in sub toxic dose 25 μg/mL during 48 h on the protein profile of human keratinocytes HaCaT was studied by tandem mass spectrometry with electrospray ionization. In total, 1064 proteins were found in immortalized human keratinocytes HaCaT, of which about 80% were identified by two or more peptides. The change of the 217 proteins content was revealed, among them 39 according to Gene Ontology are associated with oxidative stress. It has been found that sodium dodecyl sulfate leads to a decrease in the number of proteins/peptides containing carboxymethylated and/or carboxyethylated lysine. We concluded about the promising of the cells redox-balance analysis at testing chemicals in the doses, which do not lead to a decrease in their viability. Possible involvement of sodium dodecyl sulfate in the development of cutaneous neoplasia is discussed.
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Background: Gene-expression analysis is increasingly important in biological research, with real-time reverse transcription PCR (RT-PCR) becoming the method of choice for high-throughput and accurate expression profiling of selected genes. Given the increased sensitivity, reproducibility and large dynamic range of this methodology, the requirements for a proper internal control gene for normalization have become increasingly stringent. Although housekeeping gene expression has been reported to vary considerably, no systematic survey has properly determined the errors related to the common practice of using only one control gene, nor presented an adequate way of working around this problem. Results: We outline a robust and innovative strategy to identify the most stably expressed control genes in a given set of tissues, and to determine the minimum number of genes required to calculate a reliable normalization factor. We have evaluated ten housekeeping genes from different abundance and functional classes in various human tissues, and demonstrated that the conventional use of a single gene for normalization leads to relatively large errors in a significant proportion of samples tested. The geometric mean of multiple carefully selected housekeeping genes was validated as an accurate normalization factor by analyzing publicly available microarray data. Conclusions: The normalization strategy presented here is a prerequisite for accurate RT-PCR expression profiling, which, among other things, opens up the possibility of studying the biological relevance of small expression differences.
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The aim of the present study was to investigate the response of normal human skin to repeated courses of Sellotape stripping. The skin of healthy volunteers was stripped five times at 24-h intervals. Skin biopsies were taken before stripping (day 0) and on days 2, 4, 7 and 10. The responses were studied using H & E staining and an immunohistochemical analysis of several aspects of epidermal proliferation and keratinization. Although increased proliferation (nuclear binding to Ki-67 binding), acanthosis and parakeratosis were observed, the overall histological picture did not resemble psoriatic histology completely: no micropustules of Kogoj and no thinning of the suprapapillary plate were observed. Involucrin staining followed the recruitment of cycling epidermal cells showing a statistically significant elevation of positive cell layers from day 2 onwards. Filaggrin expression showed an increase from day 2 onwards, which was statistically significant on day 7 and day 10. Using the anti-keratin antibodies KS8.12 (K13 and K16) and RKSE60 (K10) we observed a fast induction of K13/K16 expression, while the staining of keratin 10 showed the same overall intensity at different time intervals. In conclusion, the response to repeated courses of tape stripping provides an adequate model for studies on epidermal proliferation, hypergranulosis and hyperkeratosis. This approach causes a more prolonged induction of these phenomena than a single course of stripping. In contrast to the situation following a single course of stripping, repeated tape stripping induced the expression of filagrin. Therefore the repeated tape stripping model is less compatible with psoriasis than a single course of stripping.
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An important component of barrier function in human epidermis is contributed by ceramides that are bound by ester linkages to undefined proteins of the cornified cell envelope (CE). In this paper, we have examined the protein targets for the ceramide attachment. By partial saponification of isolated foreskin epidermal CEs followed by limited proteolysis, we have recovered several lipopeptides. Biochemical and mass spectroscopic characterization revealed that all contained near stoichiometric amounts of ceramides of masses ranging from about 690 to 890 atomic mass units, of which six quantitatively major species were common. The array of ceramides was similar to that obtained from pig skin, the composition of which is known, thereby providing strong indirect data for their fatty acid and sphingosine compositions. The recovered peptides accounted for about 20% of the total foreskin CE ceramides. By amino acid sequencing, about 35% of the peptides were derived from ancestral glutamine-glutamate-rich regions of involucrin, an important CE structural protein. Another 18% derived from rod domain sequences of periplakin and envoplakin, which are also known or suspected CE proteins. Other peptides were too short for unequivocal identification. Together, these data indicate that involucrin, envoplakin, periplakin, and possibly other structural proteins serve as substrates for the attachment of ceramides by ester linkages to the CE for barrier function in human epidermis.
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Gene-expression analysis is increasingly important in biological research, with real-time reverse transcription PCR (RT-PCR) becoming the method of choice for high-throughput and accurate expression profiling of selected genes. Given the increased sensitivity, reproducibility and large dynamic range of this methodology, the requirements for a proper internal control gene for normalization have become increasingly stringent. Although housekeeping gene expression has been reported to vary considerably, no systematic survey has properly determined the errors related to the common practice of using only one control gene, nor presented an adequate way of working around this problem. We outline a robust and innovative strategy to identify the most stably expressed control genes in a given set of tissues, and to determine the minimum number of genes required to calculate a reliable normalization factor. We have evaluated ten housekeeping genes from different abundance and functional classes in various human tissues, and demonstrated that the conventional use of a single gene for normalization leads to relatively large errors in a significant proportion of samples tested. The geometric mean of multiple carefully selected housekeeping genes was validated as an accurate normalization factor by analyzing publicly available microarray data. The normalization strategy presented here is a prerequisite for accurate RT-PCR expression profiling, which, among other things, opens up the possibility of studying the biological relevance of small expression differences.
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Mammalian epidermis normally displays a distinctive calcium gradient, with low levels in the basal/spinous layers and high levels in the stratum granulosum. Although changes in stratum granulosum calcium regulate the lamellar body secretory response to permeability barrier alterations, whether modulations in calcium also regulate the expression of differentiation-specific proteins in vivo remains unknown. As acute barrier perturbations reduce calcium levels in stratum granulosum, we studied the regulation of murine epidermal differentiation after loss of calcium accompanying acute barrier disruption and by exposure of such acutely perturbed skin sites to either low (0.03 M) or high (1.8 M) calcium. Three hours after acute barrier disruption, coincident with reduced calcium and ultrastructural evidence of accelerated lamellar body secretion, both northern analyses and in situ hybridization revealed decreased mRNA levels for loricrin, profilaggrin, and involucrin in the outer epidermis, but protein levels did not change significantly. Moreover, exposure of acutely disrupted skin sites to low calcium solutions sustained the reduction in mRNA levels, whereas exposure to high calcium solutions restored normal mRNA levels (blocked by the L-type calcium channel inhibitor, nifedipine). Finally, with prolonged exposure to a low (<10% relative humidity) or high (>80% relative humidity) humidity, calcium levels increased and declined, respectively. Accordingly, mRNA and protein levels of the differentiation-specific markers increased and decreased at low and high relative humidity, respectively. These results provide direct evidence that acute and sustained fluctuations in epidermal calcium regulate expression of differentiation-specific proteins in vivo, and demonstrate that modulations in epidermal calcium coordinately regulate events late in epidermal differentiation that together form the barrier.
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Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of approximately 4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.
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Atopic disease, including atopic dermatitis (eczema), allergy and asthma, has increased in frequency in recent decades and now affects approximately 20% of the population in the developed world. Twin and family studies have shown that predisposition to atopic disease is highly heritable. Although most genetic studies have focused on immunological mechanisms, a primary epithelial barrier defect has been anticipated. Filaggrin is a key protein that facilitates terminal differentiation of the epidermis and formation of the skin barrier. Here we show that two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis. These variants are carried by approximately 9% of people of European origin. These variants also show highly significant association with asthma occurring in the context of atopic dermatitis. This work establishes a key role for impaired skin barrier function in the development of atopic disease.
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Evidence is growing that protease-activated receptor-2 (PAR-2) plays a key role in epithelial inflammation. We hypothesized here that PAR-2 plays a central role in epidermal permeability barrier homeostasis by mediating signaling from serine proteases (SP) in the stratum corneum (SC). Since the SC contains tryptic- and chymotryptic-like activity, we assessed the influence of SP activation/inhibition on barrier function. Acute barrier disruption increases SP activity and blockade by topical SP inhibitors (SPI) accelerates barrier recovery after acute abrogation. This improvement in barrier function is due to accelerated lamellar body (LB) secretion. Since tryptic SP signal certain downstream responses through PAR-2, we assessed its potential role in mediating the negative effects of SP on permeability barrier. Firstly, PAR-2 is expressed in the outer nucleated layers of the epidermis and most specifically under basal condition to the lipid raft (LR) domains. Secondly, tape stripping-induced barrier abrogation provokes PAR-2 activation, as shown by receptor internalization (i.e. receptor movement from LR to cytolpasmic domains). Thirdly, topical applications of PAR-2 agonist peptide, SLIGRL, delay permeability barrier recovery and inhibit LB secretion, while, conversely, PAR-2 knockout mice display accelerated barrier recovery kinetics and enhanced LB secretion, paralleled by increased LR formation and caveolin-1 expression. These results demonstrate first, the importance of SP/SPI balance for normal permeability barrier homeostasis, and second, they identify PAR-2 as a novel signaling mechanism of permeability barrier, that is, of response linked to LB secretion.
Article
In previous studies we have shown that experimental permeability barrier disruption leads to an increase in epidermal lipid and DNA synthesis. Here we investigate whether barrier disruption also influences keratins and cornified envelope proteins as major structural keratinocyte proteins. Cutaneous barrier disruption was achieved in hairless mouse skin by treatments with acetone occlusion, sodium dodecyl sulfate, or tape-stripping. As a chronic model for barrier disruption, we used essential fatty acid deficient mice. Epidermal keratins were determined by one- and two-dimensional gel electrophoresis, immunoblots, and anti-keratin antibodies in biopsy samples. In addition, the expression of the cornified envelope proteins loricrin and involucrin after barrier disruption was determined by specific antibodies in human skin. Acute as well as chronic barrier disruption resulted in the induction of the expression of keratins K6, K16, and K17. Occlusion after acute disruption led to a slight reduction of keratin K6 and K16 expression. Expression of basal keratins K5 and K14 was reduced after both methods of barrier disruption. Suprabasal keratin K10 expression was increased after acute barrier disruption and K1 as well as K10 expression was increased after chronic barrier disruption. Loricrin expression in mouse and in human skin was unchanged after barrier disruption. In contrast, involucrin expression, which was restricted to the granular and upper spinous layers in normal human skin, showed an extension to the lower spinous layers 24 h after acetone treatment. In summary, our results document that acute or chronic barrier disruption leads to expression of keratins K6, K16, and K17 and to a premature expression of involucrin. We suggest that the coordinated regulation of lipid, DNA, keratin, and involucrin synthesis is critical for epidermal permeability barrier function.Keywords: loricrin
Article
Exposure of the skin to sodium dodecyl sulfate (SDS) leads to disruption of barrier and skin irritation. We used repetitive short exposure to a low molarity SDS solution as an in vivo model to mimic the development of irritant contact dermatitis. In this model, we studied clinical (erythema), functional (transepidermal water loss(TEWL)) and cell biological changes, 24 healthy volunteers were patch tested with SDS (0.2%) for 4 h a the day for 5 consecutive days. After removal of the patches, the exposed sites were treated 1 × daily either with a topical corticosteroid (triamcinolon acetoide cream 0.05%). a retinoid (tretinoin cream 0.025%). or a vitamin D3 derivative (calcipotriol ointment 50 microgram/g). Irritant reactions were assessed by erythema scoring and measurement of barrier function with TEWL up to 14 days after the first challenge. Skin biopsies were taken for cell biological changes at day 4. Vehicle-treated sites served as controls. Repetitive exposure of human skin to SDS resulted in a gradual increase in erythema scoring and TEWL associated with the upregulation of proliferative cells as measured by the expression of Ki-67-antigen and of differentiation markers, visualized by increased expression of involucrin and epidermal-fatty-acid binding protein (E-FABP). Skin irritation as assessed by erythema scoring and TEWL was not significantly suppressed by triamcinolone cream. However, a significant reduction of the number of cycling keratinocytes and a decrease in involucrin positive cell layers was observed in this group. Neither treatment with calcipotriol ointment nor with tretinoin cream induced improvement of skin irritation as judged by visual scoring and TEWL. In contrast to steroid treatment no significant elf eel of calcipotriol ointment or tretinoin cream treatment was observed with regard to the number of cycling cells and differentiation markers. Further studies are needed to assess whether treatment with topical corticosteroids is an effective modality in skin irritation and irritant contact dermatitis.
Article
Perturbation of the cutaneous permeability barrier results in rapid secretion of epidermal lamellar bodies, and synthesis and secretion of new lamellar bodies leading to barrier repair. Since external Ca2+ significantly impedes the repair response, we applied ion capture cytochemistry to localize Ca2+ in murine epidermis following barrier disruption. In controls, the numbers of Ca2+ precipitates in the basal layer were small, increasing suprabasally and reaching the highest density in the stratum granulosum. Barrier disruption with acetone produced an immediate, marked decrease in Ca2+ in the stratum granulosum, accompanied by secretion of lamellar bodies. Loss of this pattern of Ca2+ distribution was associated with the appearance of large Ca2+ aggregates within the intercellular spaces of the stratum corneum. The Ca2+-containing precipitates progressively reappeared in parallel with barrier recovery over 24 h. Disruption of the barrier with tape stripping also resulted in loss of Ca2+ from the nucleated layers of the epidermis, but small foci persisted where the stratum corneum was not removed; in these sites the Ca2+ distribution did not change and accelerated secretion of lamellar bodies was not observed. Following acetone-induced barrier disruption and immersion in isoosmolar sucrose, the epidermal Ca2+ gradient did not return, and both lamellar body secretion and barrier recovery occurred. However, with immersion in isoosmolar sucrose plus Ca2+, the epidermal Ca2+ reservoir was replenished, and both secretion of lamellar bodies and barrier recovery were impeded. These results demonstrate that barrier disruption results in loss of the epidermal Ca2+ reservoir, which may be the signal that initiates lamellar body secretion leading to barrier repair.
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An attempt is made to formulate some kind of working hypothesis concerning the pathophysiology, clinical appearance and treatment of irritant contact dermatitis. Acute irritant dermatitis may he caused by one single overwhelming external exposure of comparatively short duration. It is usually accidental and therefore recognized early as cause and effect. Chronic irritant dermatitis may be the result of a too early repetition of one impairing factor (chronic irritant dermatitis ‘traumiteration’ type), but is more commonly the result of the influence of a variety of stimuli, each starting to be active before recovery from the foregoing stimuli has been completed (chronic irritant dermatitis ‘summation’ type). By repetition of the same stimulus, or by a combination of varying stimuli, the degree of impairment surpasses a critical level, in consequence of which a clinical disease (irritant contact dermatitis) ensues. This clinical disease, however, is only ‘the tip of the iceberg’. Such stimuli may be chemical, mechanical and/or climatic. To find out which are the harmful factors requires a detailed case history about the patient's work, habits and hobbies, thus enabling him to avoid as many damaging exposures as is practical, and hence reducing the sum of causative factors. A number of causative factors are enumerated. The article is intended to be a catalyst to promote discussion on this subject.
Article
Allergic and irritant contact dermatitis are similar clinically, histologically and on immunohistochemistry. In the present investigation, we assessed whether study of the recruitment of cycling epidermal cells, and the expression of keratin 16 and involucrin, are of use in differentiating between the response to contact allergens and the response to the irritant detergent sodium lauryl sulphate. Both allergic and irritant challenges induced epidermal proliferation, and the expression of keratin 16 and involucrin, but the dynamics were different. Two and 3 days after challenge, a highly significant difference between the allergic and irritant reactions was observed with respect to involucrin expression assessed by MON-150 staining.
Article
Two human skin recombinants, the epidermis reconstructed on the deepidermized dermis (RE-DED) or on fibroblast-populated collagen matrix (Living Skin Equivalent, LSE), were used to study the irritating effect of sodium lauryl sulfate (SLS). The extent of cytotoxicity induced after a 24-hour exposure period to increasing concentrations of SLS (0-5%) was evaluated on the basis of (1) morphological perturbations, (2) changes in the expression of differentiation-specific protein markers (keratin 1, 10, 6, 16, involucrin and transglutaminase), (3) cell membrane integrity (LDH leakage) and (4) release of proinflammatory mediators (PGE2, IL-1, IL-6 and IL-8). SLS induced significant changes in epidermal morphology and changes in the expression and localization of differentiation-specific protein markers when applied topically in concentrations higher than 1% on RE-DED and higher than 0.1% on LSE. The exposure of both human skin recombinants to SLS resulted in a dose-dependent release of LDH, PGE2 and IL-1 alpha and in an increase in keratinocyte intracellular IL-1 levels. Upon application of 5% SLS on RE-DED the total (intra- and extracellular) IL-1 levels remained high but due to cell damage the intracellular IL-1 level was markedly decreased and the extracellular IL-1 level increased. Similar observations have been made with LSE after application of 0.5% SLS. However, with LSE the extracellular IL-1 alpha levels were found to be about 100 times lower than those measured with RE-DED. Exposure of LSE to SLS induced a marked increase of IL-6 production in fibroblasts incorporated in the collagen matrix. Contrary to LSE, both intra- and extracellular levels of IL-6 were low in unexposed controls and were only marginally modulated by the exposure of the RE-DED to SLS. In addition, a dose-dependent increase in IL-8 release was observed upon application of SLS on RE-DED. The results of the present study indicate that concentrations of SLS required to induce epidermal irritancy in vitro approximate those inducing irritation in human skin in vivo. All parameters used in the present study for evaluation of toxicity can serve as useful endpoints for screening of contact skin irritancy in vitro. Compared to RE-DED, the LSE seems to be more susceptible to SLS. The differences in sensitivity between LSE and RE-DEd can be ascribed to reported differences in their stratum corneum barrier function.
Article
Exposure of the skin to sodium dodecyl sulfate (SDS) leads to disruption of barrier and skin irritation. We used repetitive short exposure to a low molarity SDS solution as an in vivo model to mimic the development of irritant contact dermatitis. In this model, we studied clinical (erythema), functional (transepidermal water loss(TEWL)) and cell biological changes. 24 healthy volunteers were patch tested with SDS (0.2%) for 4 h a day for 5 consecutive days. After removal of the patches, the exposed sites were treated 1 X daily either with a topical corticosteroid (triamcinolon acetonide cream 0.05%), a retinoid (tretinoin cream 0.025%), or a vitamin D3 derivative (calcipotriol ointment 50 micrograms/g). Irritant reactions were assessed by erythema scoring and measurement of barrier function with TEWL up to 14 days after the first challenge. Skin biopsies were taken for cell biological changes at day 4. Vehicle-treated sites served as controls. Repetitive exposure of human skin to SDS resulted in a gradual increase in erythema scoring and TEWL associated with the upregulation of proliferative cells as measured by the expression of Ki-67-antigen and of differentiation markers, visualized by increased expression of involucrin and epidermal-fatty-acid binding protein (E-FABP). Skin irritation as assessed by erythema scoring and TEWL was not significantly suppressed by triamcinolone cream. However, a significant reduction of the number of cycling keratinocytes and a decrease in involucrin positive cell layers was observed in this group. Neither treatment with calcipotriol ointment nor with tretinoin cream induced improvement of skin irritation as judged by visual scoring and TEWL. In contrast to steroid treatment, no significant effect of calcipotriol ointment or tretinoin cream treatment was observed with regard to the number of cycling cells and differentiation markers. Further studies are needed to assess whether treatment with topical corticosteroids is an effective modality in skin irritation and irritant contact dermatitis.
Article
We have studied the effect of various detergents on keratinocyte gene expression in vitro, using an anionic detergent (sodium dodecyl sulfate), a cationic detergent cetyltrimethylammoniumbromide (CTAB), and two nonionic detergents, Nonidet P-40 and Tween-20. We measured the effect of these detergents on direct cellular toxicity (lactate dehydrogenase release), on the expression of markers for normal differentiation (cytokeratin 1 and involucrin expression), and on disturbed keratinocyte differentiation (SKALP) by northern blot analysis. As reported in other studies, large differences were noted in direct cellular toxicity. In a culture model that mimics normal epidermal differentiation we found that low concentrations of sodium dodecyl sulfate could induce the expression of SKALP, a proteinase inhibitor that is not normally expressed in human epidermis but is found in hyperproliferative skin. Sodium dodecyl sulfate caused upregulation of involucrin and downregulation of cytokeratin 1 expression, which is associated with the hyperproliferative/inflammatory epidermal phenotype found in psoriasis, wound healing, and skin irritation. These changes were not induced after treatment of cultures with CTAB, Triton X-100, and Nonidet-P40. This effect appeared to be specific for the class of anionic detergents because sodium dodecyl benzene sulfonate and sodium laurate also induced SKALP expression. These in vitro findings showed only a partial correlation with the potential of different detergents to induce clinical, biophysical, and cell biologic changes in vivo in human skin. Both sodium dodecyl sulfate and CTAB were found to cause induction and upregulation of SKALP and involucrin at low doses following a 24 h patch test, whereas high concentrations of Triton X-100 did not. Sodium dodecyl sulfate induced higher rates of transepidermal water loss, whereas CTAB treated skin showed more signs of cellular toxicity. We conclude that the action of anionic detergents on epidermal keratinocytes is qualitatively different from the other detergents tested, which might have implications for in vitro toxicology studies that use cell biologic parameters as a read-out. We would hypothesize that detergents cause skin injury by several mechanisms that include direct cellular toxicity, disruption of barrier function, and detergent specific effects on cellular differentiation, as demonstrated here for sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, and sodium laurate.
Article
Stratum corneum chymotryptic enzyme may be important in desquamation. It has also been suggested that other proteases, especially stratum corneum tryptic enzyme, may be involved. Stratum corneum tryptic enzyme has been purified and its cDNA has been cloned. Results from expression analyses indicate that stratum corneum tryptic enzyme is as skin specific as stratum corneum chymotryptic enzyme. In this work we have produced and characterized antibodies specific for stratum corneum tryptic enzyme. We have also by means of biochemical, immunochemical, and immunohistochemical methods performed studies on stratum corneum tryptic enzyme in normal human epidermis. Antibodies against bacterial recombinant stratum corneum tryptic enzyme were produced and purified by affinity chromatography. Two types of antibodies were obtained: one reacting only with pro-stratum corneum tryptic enzyme and one specific for the catalytically active part of stratum corneum tryptic enzyme. Immunohistochemistry with the antibodies reacting with pro-stratum corneum tryptic enzyme showed a staining pattern similar to stratum corneum chymotryptic enzyme-specific antibodies, i.e., the expression was confined to cornifying epithelia with a need of desquamation-like processes. Extracts of tape strips with superficial human stratum corneum were found to contain precursors as well as active forms of stratum corneum tryptic enzyme and stratum corneum chymotryptic enzyme. The enzymes had maximal activity at pH 8, but both had considerable activity also at pH 5.5. The results were compatible for a role of stratum corneum tryptic enzyme in desquamation. Stratum corneum tryptic enzyme may act in concert with stratum corneum chymotryptic enzyme and/or function as a stratum corneum chymotryptic enzyme-activating enzyme. The presence in normal superficial stratum corneum of precursors as well as of active forms of stratum corneum chymotryptic enzyme and stratum corneum tryptic enzyme, and the activity of both enzymes over a broad range of pH-values, suggest some possible ways by which the desquamation may be regulated.
Article
Filaggrin is an intermediate filament (IF)-associated protein that aggregates keratin IFs in vitro and is thought to perform a similar function during the terminal differentiation of epidermal keratinocytes. To further explore the role of filaggrin in the cytoskeletal rearrangement that accompanies epidermal differentiation, we generated keratinocyte cell lines that express human filaggrin using a tetracycline-inducible promoter system. Filaggrin expression resulted in reduced keratinocyte proliferation and caused an alteration in cell cycle distribution consistent with a post-G1 phase arrest. Keratin filament distribution was disrupted in filaggrin-expressing lines, while the organization of actin microfilaments and microtubules was more mildly affected. Evidence for direct interaction of filaggrin and keratin IFs was seen by overlay assays of GFP-filaggrin with keratin proteins in vitro and by filamentous filaggrin distribution in cells with low levels of expression. Cells expressing moderate to high levels of filaggrin showed a rounded cell morphology, loss of cell-cell adhesion, and compacted cytoplasm. There was also partial or complete loss of the desmosomal proteins desmoplakin, plakoglobin, and desmogleins from cell-cell borders, while the distribution of the adherens junction protein E-cadherin was not affected. No alterations in keratin cytoskeleton, desmosomal protein distribution, or cell shape were observed in control cell lines expressing beta-galactosidase. Filaggrin altered the cell shape and disrupted the actin filament distribution in IF-deficient SW13 cells, demonstrating that filaggrin can affect cell morphology independent of the presence of a cytoplasmic IF network. These studies demonstrate that filaggrin, in addition to its known effects on IF organization, can affect the distribution of other cytoskeletal elements including actin microfilaments, which can occur in the absence of a cytoplasmic IF network. Further, filaggrin can disrupt the distribution of desmosome proteins, suggesting an additional role(s) for this protein in the cytoskeletal and desmosomal reorganization that occurs at the granular to cornified cell transition during terminal differentiation of epidermal keratinocytes.
Article
Little is known of the predictive value of methods to test an individual's susceptibility to acquiring occupational contact dermatitis. Recently, the recovery rate after induced irritation was suggested for this purpose. Although it is likely that repeated exposure to sodium lauryl sulphate (SLS) is preferable to a single application, there is little evidence to support this idea. Similarly, little is known about whether the outcome of a repeated SLS test can be predicted by a brief test. We studied the relationship between the skin reaction after a repeated SLS test and two brief tests, devoting special attention to the recovery rate. In 29 healthy volunteers, we measured transepidermal water loss (TEWL) and erythema after applying 0.03, 0.1 and 0.3% SLS for 6 h, 3 days per week, over a course of 3 weeks. The data were compared with the effects after applying 0.1, 0.3 and 1.0% SLS for 24 h and with 10 and 15 repetitions of tape stripping. A poor correlation was found between the repeated test and the brief SLS test, or tape stripping, when using an increase in TEWL (r = 0.04 and 0.26, respectively) or its recovery rate (r = - 0.01 and 0.42, respectively). We presume that in a repeated test of sufficient duration, additional mechanisms come into play that are absent in a brief test, e.g. an alteration in the thickness of the epidermis, with a resulting change in the permeability of SLS. When such an effect differs between subjects it could explain the lack of agreement between the acute and the repeated tests. At present, a brief irritation test will, in all likelihood, be unable to assess an individual's susceptibility to occupational contact dermatitis.
Article
A defective permeability barrier leads to the penetration of environmental allergens into the skin and initiates immunological reactions and inflammation crucially involved in the pathogenesis of atopic dermatitis (AD). Decreased stratum corneum ceramide content may cause the defect in permeability barrier function consistently found in AD. Acid and neutral sphingomyelinase (A- and N-SMase) generate ceramides with structural and signal transduction functions in epidermal proliferation and differentiation. We determined epidermal SMase activities, DNA synthesis, involucrin, loricrin, filaggrin, and keratin expression in lesional and non-lesional skin of AD patients. We found decreased epidermal A-SMase activity in lesional and non-lesional skin, correlating with reduced stratum corneum ceramide content and disturbed barrier function. N-SMase activity was reduced in non-lesional skin and more significantly reduced in lesional skin, correlating with impaired expression of cornified envelope proteins and keratins, important for skin barrier function. Changes in involucrin, loricrin, filaggrin, keratin K 5 (basal) and K 16 (proliferation associated) were noticed in non-lesional and lesional skin, whereas changes in K 10 (suprabasal), K 6 (proliferation associated), and K 17 (inflammation associated) were found only in lesional skin. In summary, reduction in SMase-generating ceramides and impaired differentiation are involved in the defective barrier function found in AD.
Article
We showed recently that short-term increases in stratum corneum (SC) pH are accompanied by minor alterations in permeability barrier homeostasis and SC integrity/cohesion. Since prolonged SC neutralization more closely mirrors clinical situations (i.e., neonatal skin, occupational dermatitis conditions), we assessed here whether sustained elevations of SC pH by long-term application of 1,1,3,3-tetramethylguanidine superbase provoke profound alterations in SC function. Sustained SC neutralization altered not only barrier recovery kinetics but also basal permeability barrier function. These abnormalities were attributable to a decrease in beta-glucocerebrosidase (beta-GlcCer'ase) and acidic sphingomyelinase (aSMase) catalytic activity and enzyme degradation consequent to a pH-induced sustained serine protease (SP) activity. The role of SP in this process was shown by the normalization of enzyme activities/content by co-applied SP inhibitors (SPI). To address whether lipid-processing enzymes are potential substrates for the stratum corneum chymotryptic enzyme (SCCE), protein extracts from human SC were treated for 2 h at 37 degrees C with recombinant active SCCE at pH 7.2. Recombinant SCCE induced a significant decrease in the immunoblotting of both beta-GlcCer'ase or aSMase compared with control experiments performed in the absence of the active SCCE. Finally, with sustained SC neutralization, SC integrity/cohesion deteriorated, attributable to SP-mediated degradation of corneodesmosomes (CD) as well as CD constituent proteins, desmoglein 1. These abnormalities were again reversed by co-applied SPI. In conclusion, prolonged SC neutralization provokes profound abnormalities in SC function, due to pH-induced high SP activity that, in turn, degrades lipid processing enzymes and CD proteins.
Article
Profilaggrin is a key epidermal protein, critical for the generation and maintenance of the stratum corneum barrier. It is encoded by a gene located in the epidermal differentiation complex of Chromosome 1q21 and is composed of multiple filaggrin repeats connected by highly conserved linker peptides. Within the human population the number of filaggrin repeats encoded by this gene varies between 10, 11 or 12 repeats. Using a PCR-based approach we have determined individual profilaggrin allelotypes in a group of 113 subjects and identified preliminary evidence of an inverse association between the 12 repeat allele and self-perceived frequent dry skin (P=0.0293). This is the first demonstration of a potential association between a genetic marker and cosmetic skin condition and suggests that cosmetic skin dryness may in part be genetically determined and associated with specific profilaggrin allelotypes.
Article
Detergents are well known irritants. Effects of the detergent sodium lauryl sulphate (SLS) on cell toxicity using the XTT assay and mRNA expression of inflammatory mediators, markers of keratinocyte differentiation and enzymes synthesizing barrier lipids using real-time PCR were studied in cultured differentiated keratinocytes. After exposure for 24 h to SLS concentrations at 0.002% or above, toxic effects were observed. When a lower SLS concentration (0.00075%) was used the mRNA expression of inflammatory mediators peaked around 4-8 h. The expression of enzymes involved in the synthesis of cholesterol, fatty acids and ceramides and markers of keratinocyte differentiation also increased but after 24 h. In cells exposed to 0.000125-0.0015% SLS, a concentration-dependent induction of the expression of inflammatory mediators was found after 4 h. Similar changes were found after 24 h for involucrin and enzymes involved in ceramide synthesis. The mRNA expression of HMG-CoA synthase and reductase, long-chain acyl-CoA synthase and transglutaminase also peaked after 24 h, but maximal induction was observed already at 0.00075% SLS. In conclusion, SLS induces an inflammatory response in keratinocytes and alters the mRNA expression of important barrier lipid enzymes and markers of keratinocyte differentiation, of possible importance for the irritant properties of SLS.
Article
The analysis of EpiDerm cultures treated with the known skin irritant sodium lauryl sulphate (SLS) was performed using 2D-gel electrophoresis in order to understand the mechanism of action and thereby identify novel markers of skin irritation. A range of both broad and narrow pH gradient first-dimension gels were run (pH 4-7, 6-11, 4-5, 5-6 and 6-9) consistently followed by 12% SDS-PAGE in the second-dimension. Following treatment of EpiDerm with SLS, 67 proteins of interest were identified, of which 8 were selected as interesting: calmodulin-like skin protein, involucrin, epithelial cell marker protein, HS1, peroxiredoxin 1, serine protease inhibitor, KIAA0117 and ribosomal protein L17. Involucrin was confirmed as being up-regulated by both ELISA and Western blotting. The use of proteomics has identified a number of proteins which could be used as general markers for skin irritation and which may in particular be of value for the development of in vitro predictive models.
Understanding the irritant reaction
  • Willis
Willis C, Lindberg M (2004) Understanding the irritant reaction. In: Skin, hair and nails. Structure and function. (Forslind B, Lindberg M, eds), New York: Marcel & Dekker, 233-72
Repeated tape stripping of normal skin: a histological assessment and comparison with events seen in psoriasis
  • Gerritsen