Epidermal Barrier Disruption Research Articles

Novel therapies in the treatment of atopic dermatitis.

Atopic dermatitis (AD) is a common cutaneous condition characterized by epidermal barrier disruption, severe skin inflammation, and pruritus. As a result of our growing understanding of disease pathogenesis, the therapeutic armamentarium to manage AD is rapidly expanding. Moving beyond broadly immunosuppressive agents, newer therapies for AD offer more targeted immunomodulation in the forms of phosphodiesterase 4 inhibitors, Janus kinase inhibitors, and anticytokine monoclonal antibodies. While such therapies are generally considered safer than traditional immunosuppressive agents that have been used off label for AD for decades, they are not without risk entirely. In some cases, potential side effects may be difficult to manage. This review summarizes current views on AD pathogenesis and discusses these novel and emerging therapies, including a discussion of the mechanisms of action, potential side effects, and limitations of current clinical trials for each drug. While the rapid and prolific expansion of therapies to treat AD is encouraging, additional studies are needed to adequately evaluate the long-term safety, efficacy, and generalizability among different age groups and disease subtypes.

Atopic dermatitis.

Atopic dermatitis (AD) is the most common chronic inflammatory skin disease, with a lifetime prevalence of up to 20% and substantial effects on quality of life. AD is characterized by intense itch, recurrent eczematous lesions and a fluctuating course. AD has a strong heritability component and is closely related to and commonly co-occurs with other atopic diseases (such as asthma and allergic rhinitis). Several pathophysiological mechanisms contribute to AD aetiology and clinical manifestations. Impairment of epidermal barrier function, for example, owing to deficiency in the structural protein filaggrin, can promote inflammation and T cell infiltration. The immune response in AD is skewed towards T helper 2 cell-mediated pathways and can in turn favour epidermal barrier disruption. Other contributing factors to AD onset include dysbiosis of the skin microbiota (in particular overgrowth of Staphylococcus aureus), systemic immune responses (including immunoglobulin E (IgE)-mediated sensitization) and neuroinflammation, which is involved in itch. Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants. Translational research has fostered the development of targeted small molecules and biologic therapies, especially for moderate-to-severe disease.

Epidermal barrier disruption by 9-hydroxy-10E,12Z-octadecadienoic acid in human keratinocytes.

Epidermal barrier disruption by 9-hydroxy-10E,12Z-octadecadienoic acid in human keratinocytes.

887 Trichophyton rubrum infection on reconstructed human epidermis induces simultaneous epidermal barrier disruption and keratinocytes activation

887 Trichophyton rubrum infection on reconstructed human epidermis induces simultaneous epidermal barrier disruption and keratinocytes activation

Disruption of the Epidermal Barrier Induces Regulatory T Cells via IL-33 in Mice

Disturbance of the epidermal barrier by UVR is associated with the release of antimicrobial peptides and inflammatory cytokines for the purpose of a danger response. On the other hand, UVR causes immunosuppression via regulatory T cells (Treg) that limit the inflammatory reaction. The concurrent induction of antimicrobial peptides and Treg by UVR may represent a counter-regulatory mechanism in response to barrier disruption, preventing microbial superinfection and sensitization to contact allergens, respectively, both of which cross impaired epidermis more easily. Thus, using a model of murine contact hypersensitivity we examined if disruption of the epidermal barrier only initiates similar counter-regulatory mechanisms via the generation of Treg. Sensitization through tape-stripped skin induced a weaker contact hypersensitivity response than in control mice. This was due to the induction of antigen-specific Treg, as demonstrated in adoptive transfer and depletion experiments utilizing DEREG mice. Treg induction by tape stripping was linked to the expression of the alarmin IL-33, as blockade of IL-33 exacerbated contact hypersensitivity, whereas injection of IL-33 inhibited contact hypersensitivity and induced Treg. These results demonstrate that epidermal barrier disruption, in addition to danger signals, induces regulatory events that prevent exaggerated skin inflammation and that IL-33 appears to be critically involved in this process.

Identification of unique proteomic signatures in allergic and non-allergic skin disease.

Atopic dermatitis (AD), psoriasis (PS), and contact dermatitis (CD) are common skin diseases, characterized by barrier disruption and systemic inflammation, with unique epidermal signatures and common inflammatory pathways identified by transcriptomic profiling. This study profiled proteomic signatures in serum from subjects with AD, PS, and CD compared with healthy controls (HC). Identify unique proteomic signatures to distinguish between inflammatory diseases with similar epidermal disruption and overlapping epithelial inflammation. Sera from 20 subjects with moderate to severe AD, 10 subjects with CD, 12 subjects with moderate to severe PS, 10 subjects with both AD and CD, and 10 HC with no history of skin disease was analysed using high-throughput proteomic analysis that detects expression of 1129 protein targets. Protein expression was compared between disease and HC, and across diseases for statistical significance (fold change≥1.5 and false discovery rate≤0.05), to identify unique proteomic signatures for each disease. Complement C5A anaphylatoxin (C5A), lipopolysaccharide binding protein (LBP), C-reactive protein (CRP), ILT-4, C-C motif ligand 18 (PARC), and sialic acid-binding Ig-like lectin 14 (SIG14) were significantly modulated in all three diseases compared with HC. We identified unique signatures for AD (Immunoglobulin E (IgE), thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC)), CD (10 proteins), and PS (kynureninase (KYNU)). Proteomic profiling in subjects with both AD and CD identified additional dysregulated proteins compared with subjects with either condition alone, indicating an exacerbated inflammation reaction. Unique sera proteomic signatures may distinguish between inflammatory skin diseases despite similar epidermal barrier disruption and epithelial inflammation. This may provide insight into disease pathogenesis, diagnosis, and therapeutic intervention in difficult-to-treat subjects.

Inflammatory and Noninflammatory Itch: Implications in Pathophysiology-Directed Treatments.

Itch is the main chief complaint in patients visiting dermatologic clinics and has the ability to deeply impair life quality. Itch results from activation of cutaneous nerve endings by noxious stimuli such as inflammatory mediators, neurotransmitters and neuropeptides, causing itch signal transduction from peripheral skin, through the spinal cord and thalamus, to the brain cortex. Primarily noninflammatory diseases, such as uremic pruritus, cause itch through certain pruritogens in the skin. In inflammatory skin diseases, atopic dermatitis (AD) is the prototypic disease causing intensive itch by aberrant skin inflammation and epidermal barrier disruption. Recent understanding of disease susceptibility, severity markers, and mechanisms have helped to develop targeted therapy for itch in AD, including monoclonal antibodies against IL-4, IL-13, thymic stromal lymphopoietin (TSLP), IgE and IL-31. Promising effects have been observed in some of them. In this review, we summarized targeted therapies for inflammatory itch in AD and for managing abnormal itch transductions in other common itching skin diseases.

Hair Growth Cycle Is Arrested in SCD1 Deficiency by Impaired Wnt3a-Palmitoleoylation and Retrieved by the Artificial Lipid Barrier

Stearoyl-CoA desaturase 1 (SCD1) is the dominant member of the SCD-isozyme family, regarded as a major regulator of lipid and energy metabolism in liver and adipose tissue. SCD1 deficiency impairs the desaturation of de novo-synthesized palmitoyl- and stearoyl-CoA to palmitoleoyl- and oleoyl-CoA. Scd1-/- mice develop metabolic waste syndrome and skin lesions: epidermal barrier disruption, alopecia, and degeneration of sebaceous glands. The unifying molecular link between the two divergent traits remains incompletely understood. Here we show the absence of palmitoleic acid (9Z-16:1) in the lipidome of the scd1-null mouse, which prohibits posttranslational O-palmitoleoylation of Wnt3a protein, essential for Wnt3a/ß-catenin signaling in stem cell lineage decision in development of the epidermal barrier, hair growth cycle, and sebaceous glands. Substitution of the disrupted epidermal lipid barrier by an inert hydrocarbon coat prevents excessive transepidermal water loss, normalizes thermogenesis and metabolic parameters, and surprisingly leads to the activation of hair bulge progenitor cells and reprograming of a regular hair growth cycle and development of a regular fur in scd1-/- mice. Progenitor sebocytes are not activated. Independent of age, application or removal of the artificial lipid barrier allows the reversible telogen-anagen reentry and exit of the hair growth cycle.

Permeability of skin to silver nanoparticles after epidermal skin barrier disruption in rats

Permeability of skin to silver nanoparticles after epidermal skin barrier disruption in rats

Epicutaneous Sensitization in Patients with Atopic Dermatitis.

Atopic dermatitis (AD) is the most common chronic skin disorder among infants and young children. It is characterized by chronic relapsing eczema with itch and is caused by skin barrier dysfunction and immunological dysregulation. Scratching of the lesion site can damage the skin and increase epithelial permeability, thereby allowing large molecular weight antigens to be absorbed transcutaneously. However, a recent study demonstrated that Langerhans cells are localized close below the skin surface and extend dendrites vertically to penetrate the tight junctions (TJs) in erythematous lesions, even though the TJs were functionally intact. Therefore, epidermal barrier disruption per se is not critical for antigen uptake by Langerhans cells. In contrast, 2 critical damage-associated patterns-IL-33 and IL-1alpha-are reportedly released from damaged epithelial cells. Dendritic cells activated by IL-33 and thymic stromal lymphopoietin (TSLP) (induced by IL-1 alpha) express MHC class II and costimulatory molecules and facilitate naive T cell differentiation into IL-5- and IL-13-secreting Th2 cells. IL-33 and TSLP also activate type 2 innate lymphoid cells, induce large amounts of IL-5 and IL-13, and participate in the pathogenesis of AD. Primary prevention and proactive treatment of AD are critically important for preventing epicutaneous sensitization in AD patients. However, future studies are required to elucidate the most beneficial primary prevention strategies, including the indicated patient cohort and the timing and method of their application.

A synthetic C16 omega-hydroxyphytoceramide improves skin barrier functions from diversely perturbed epidermal conditions.

Omega-hydroxyceramides (ω-OH-Cer) play a crucial role in maintaining the integrity of skin barrier. ω-OH-Cer are the primary lipid constituents of the corneocyte lipid envelope (CLE) covalently attached to the outer surface of the cornified envelope linked to involucrin to become bound form lipids in stratum corneum (SC). CLE becomes a hydrophobic impermeable layer of matured corneocyte preventing loss of natural moisturizing factor inside the corneocytes. More importantly, CLE may also play an important role in the formation of proper orientation of intercellular lipid lamellar structure by interdigitating with the intercellular lipids in a comb-like fashion. Abnormal barrier conditions associated with atopic dermatitis but also UVB-irradiated skins are known to have lowered level of bound lipids, especially ω-OH-Cer, which indicate that ω-OH-Cer play an important role in maintaining the integrity of skin barrier. In this study, protective effects of a novel synthetic C16 omega-hydroxyphytoceramides (ω-OH-phytoceramide) on skin barrier function were investigated. Epidermal barrier disruption was induced by UVB irradiation, tape-stripping in hairless mouse and human skin. Protective effect of damaged epidermis was evaluated using the measurement of transepidermal water loss and cohesion of SC. Increased keratinocyte differentiation was verified using cultured keratinocyte through western blot. Results clearly demonstrated that a synthetic C16 ω-OH-phytoceramide enhanced the integrity of SC and accelerated the recovery of damaged skin barrier function by stimulating differentiation process. In a conclusion, a synthetic C16 ω-OH-phytoceramide treatment improved epidermal homeostasis in several disrupted conditions.

Photobiomodulatory effects of superpulsed 904 nm laser therapy on bioenergetics status in burn wound healing

Burn wounds exhibit impaired healing as the progression through the normal sequential stages of tissue repair gets hampered by epidermal barrier disruption, compromised blood circulation, abrogated defence mechanism, pathologic inflammation, and septicemia. Our earlier results reported that superpulsed 904nm LLLT enhanced healing and attenuated inflammatory response in burn wounds. The present study investigated the effect of superpulsed 904nm LLLT (200ns pulse width; 100Hz; 0.7mW mean output power; 0.4mW/cm2 average irradiance) on biochemical and molecular markers pertaining to bioenergetics and redox homeostasis on full-thickness burn wounds in experimental rats. Results indicated that superpulsed laser irradiation for 7days post-wounding propelled the cellular milieu towards aerobic energy metabolism as evidenced by significantly enhanced activities of key energy regulatory enzymes viz. HK, PFK, CS and G6PD, whereas LDH showed reduced activity as compared to the non-irradiated controls. LLLT showed a significant increased CCO activity and ATP level. Moreover, LLLT also regulated redox homeostasis as evidenced by enhanced NADPH levels and decreased NADP/NADPH ratio. Western blot analysis demonstrated that LLLT produced an up-regulation of GLUT1, pAMPKα and down-regulation of glycogen synthase1 (GS1). Our findings suggest that superpulsed 904nm LLLT augments burn wound healing by enhancing intracellular energy contents through modulation of aerobic metabolism for maximum energy output. Bioenergetic activation and maintenance of redox homeostasis could be one of the noteworthy mechanisms responsible for the beneficial NIR photobiomodulatory effect mediated through superpulsed 904nm LLLT in burn wound healing.

Gene loss in keratinization programs accompanies adaptation of cetacean skin to aquatic lifestyle.

Gene loss in keratinization programs accompanies adaptation of cetacean skin to aquatic lifestyle.

Epidemiology, medical genetics, diagnosis and treatment of harlequin ichthyosis in Japan.

Ichthyoses are a group of disorders marked by whitish, brown or dark-brown scales on the skin of almost the whole body. Harlequin ichthyosis (HI) is the most severe form. Neonatal death from HI was once common. Due to intensive neonatal care and, probably, to the early introduction of oral retinoids, HI outcome has improved. For definitive diagnosis and the exclusion of other disorders, such as lamellar ichthyosis, which also shows a collodion baby phenotype, it is helpful to refer to electron microscopy of abnormal or absent lamellar granules and a heavy accumulation of lipid droplets in the keratinocytes. ATP-binding cassette transporter A12 (ABCA12) is known as the causative gene of HI. Severe ABCA12 deficiency results in malformation of intercellular lipid layers in the cornified layers and leads to epidermal lipid barrier disruption. In HI patients, at least one mutation on each allele must be a truncation or deletion mutation to cause serious loss of ABCA12 function. Identification of the gene underlying HI has enabled DNA-based prenatal diagnosis for HI at the earlier stages of pregnancy with low risk. There are no curative treatments for HI. Abca12-deficient mice were created as a model of HI. Treatment of the model mice with retinoid or steroid has not been successful.

Psoriasis as a barrier disease

Skin is equipped with a barrier function, in particular, to prevent invasion of pathogens. Skin barrier is composed of a mechanical barrier, a permeability barrier, and innate and adaptive immunity barriers. Psoriasis is an inflammatory skin disease, which develops through the interaction of epidermal keratinocytes and immune cells, although its pathoetiology has not been fully understood. Recent studies revealed that defects in epidermal barrier-related genes were associated with a risk of psoriasis. Indeed, psoriasis is characterized by compromised barrier function, similar to atopic dermatitis (AD), in which mutations of the filaggrin gene play a role. However, it remains to be determined whether epidermal barrier disruption leads to an altered inflammatory/immunological response in psoriasis. In this review, I demonstrate evidence, in human psoriasis as well as mouse models, showing that barrier insult contributes to psoriasis development through alteration of the innate and adaptive immunity.

Comparative effect of dietary borage oil and safflower oil on anti-proliferation and ceramide metabolism in the epidermis of essential fatty acid deficient guinea pigs

Purpose: Borage oil (BO) and safflower oil (SO) are efficacious in reversing epidermal hyperproliferation, which is caused by the disruption of epidermal barrier. In this study, we compared the antiproliferative effect of dietary BO and SO. Altered metabolism of ceramide (Cer), the major lipid of epidermal barrier, was further determined by measurement of epidermal levels of individual Cer, glucosylceramide (GlcCer), and sphingomyelin (SM) species, and protein expression of Cer metabolizing enzymes. Methods: Epidermal hyperproliferation was induced in guinea pigs by a hydrogenated coconut diet (HCO) for 8 weeks. Subsequently, animals were fed diets of either BO (group HCO + BO) or SO (group HCO + SO) for 2 weeks. As controls, animals were fed BO (group BO) or HCO (group HCO) diets for 10 weeks. Results: Epidermal hyperproliferation was reversed in groups HCO + BO (67.6% of group HCO) and HCO + SO (84.5% of group HCO). Epidermal levels of Cer1/2, GlcCer-A/B, and β-glucocerebrosidase (GCase), an enzyme of GlcCer hydrolysis for Cer generation, were higher in group HCO + BO than in group HCO, and increased to levels similar to those of group BO. In addition, epidermal levels of SM1, serine palmitoyltransferase (SPT), and acidic sphingomyelinase (aSMase), enzymes of de novo Cer synthesis and SM hydrolysis for Cer generation, but not of Cer3-7, were higher in group HCO + BO than in group HCO. Despite an increase of SPT and aSMase in group HCO + SO to levels higher than in group HCO, epidermal levels of Cer1-7, GlcCer-A/B, and GCase were similar in these two groups. Notably, acidic ceramidase, an enzyme of Cer degradation, was highly expressed in group HCO + SO. Epidermal levels of GlcCer-C/D and SM-2/3 did not differ among groups. Conclusion: Dietary BO was more prominent for reversing epidermal hyperproliferation by enhancing Cer metabolism with increased levels of Cer1/2, GlcCer-A/B, and SM1 species, and of GCase proteins.

Comparing safety of abrasion and tape-stripping as skin preparation in allergen-specific epicutaneous immunotherapy

Comparing safety of abrasion and tape-stripping as skin preparation in allergen-specific epicutaneous immunotherapy

76 Less common indications for LLLT

Burn wounds exhibit impaired healing as the progression through the normal sequential stages of tissue repair gets hampered by epidermal barrier disruption, compromised blood circulation, abrogated defence mechanism, pathologic inflammation, and septicemia. Our earlier results reported that superpulsed 904 nm LLLT enhanced healing and attenuated inflammatory response in burn wounds. The present study investigated the effect of superpulsed 904 nm LLLT (200 ns pulse width; 100 Hz; 0.7 mW mean output power; 0.4 mW/cm2 average irradiance) on biochemical and molecular markers pertaining to bioenergetics and redox homeostasis on full-thickness burn wounds in experimental rats. Results indicated that superpulsed laser irradiation for 7 days post-wounding propelled the cellular milieu towards aerobic energy metabolism as evidenced by significantly enhanced activities of key energy regulatory enzymes viz. HK, PFK, CS and G6PD, whereas LDH showed reduced activity as compared to the non-irradiated controls. LLLT showed a significant increased CCO activity and ATP level. Moreover, LLLT also regulated redox homeostasis as evidenced by enhanced NADPH levels and decreased NADP/NADPH ratio. Western blot analysis demonstrated that LLLT produced an up-regulation of GLUT1, pAMPKα and down-regulation of glycogen synthase1 (GS1). Our findings suggest that superpulsed 904 nm LLLT augments burn wound healing by enhancing intracellular energy contents through modulation of aerobic metabolism for maximum energy output. Bioenergetic activation and maintenance of redox homeostasis could be one of the noteworthy mechanisms responsible for the beneficial NIR photobiomodulatory effect mediated through superpulsed 904 nm LLLT in burn wound healing.

78 Photodynamic therapy in treating peritonitis (experimental study)

Burn wounds exhibit impaired healing as the progression through the normal sequential stages of tissue repair gets hampered by epidermal barrier disruption, compromised blood circulation, abrogated defence mechanism, pathologic inflammation, and septicemia. Our earlier results reported that superpulsed 904 nm LLLT enhanced healing and attenuated inflammatory response in burn wounds. The present study investigated the effect of superpulsed 904 nm LLLT (200 ns pulse width; 100 Hz; 0.7 mW mean output power; 0.4 mW/cm2 average irradiance) on biochemical and molecular markers pertaining to bioenergetics and redox homeostasis on full-thickness burn wounds in experimental rats. Results indicated that superpulsed laser irradiation for 7 days post-wounding propelled the cellular milieu towards aerobic energy metabolism as evidenced by significantly enhanced activities of key energy regulatory enzymes viz. HK, PFK, CS and G6PD, whereas LDH showed reduced activity as compared to the non-irradiated controls. LLLT showed a significant increased CCO activity and ATP level. Moreover, LLLT also regulated redox homeostasis as evidenced by enhanced NADPH levels and decreased NADP/NADPH ratio. Western blot analysis demonstrated that LLLT produced an up-regulation of GLUT1, pAMPKα and down-regulation of glycogen synthase1 (GS1). Our findings suggest that superpulsed 904 nm LLLT augments burn wound healing by enhancing intracellular energy contents through modulation of aerobic metabolism for maximum energy output. Bioenergetic activation and maintenance of redox homeostasis could be one of the noteworthy mechanisms responsible for the beneficial NIR photobiomodulatory effect mediated through superpulsed 904 nm LLLT in burn wound healing.

Inflammatory peeling skin syndrome caused a novel mutation in CDSN

Generalized peeling skin syndrome (PSS) is a rare autosomal recessive dermatosis manifesting with continuous exfoliation of the stratum corneum. The inflammatory (type B) subtype of PSS was recently found to be caused by deleterious mutations in the CDSN gene encoding corneodesmosin, a major component of desmosomal junctions in the uppermost layers of the epidermis. In the present study, we assessed a 10-month-old baby, who presented with generalized superficial peeling of the skin. Using PCR amplification and direct sequencing, we identified the third PSS-associated mutation in CDSN, a homozygous 4bp duplication in the second exon of the gene (c.164_167dup GCCT; p.Thr57ProfsX6). These data further support the notion that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis, paving the way for an abnormal inflammatory response due to epidermal barrier disruption.