Linoleate-Containing Acylglucosylceramide, Acylceramide, and Events Associated with Formation of the Epidermal Permeability Barrier.

BACKGROUND: Linoleate-containing acylglucosylceramide (GLC-CER[EOx], where x = sphingosine [S], dihydrosphingosine [dS], phytosphingosine (P), or 6-hydroxysphingosine [H]) in the viable epidermis serve as the precursors to the linoleate-containing acylceramides (CER[EOx]) in the stratum corneum (SC) and the corneocyte lipid envelope (CLE), both of which are essential for the barrier function of the skin. SUMMARY: CLE formation and envelope maturation take place across the SC. Hypoxic conditions in the epidermis and anaerobic glycolysis with the production of lactic acid are important in proper SC barrier formation. KEY MESSAGE: CLE formation takes place across the SC. Its formation from linoleate-containing GLC-CER[EOx] requires lipoxygenase action, but anaerobic conditions leading to lactate production and hypoxia-inducible factors are essential for proper barrier formation. A number of unanswered questions are raised regarding formation of the CLE and the epidermal permeability barrier.

Synopsis of Barrier Function of Skin and Mucosa-Volume 2.

This is an attempt to briefly summarize the contributions to this second Special Issue of the International Journal of Molecular Sciences on the barrier function of the skin and the oral mucosa [...].

Protective Barriers Provided by the Epidermis.

The skin is the largest organ of the body and consists of an epidermis, dermis and subcutaneous adipose tissue. The skin surface area is often stated to be about 1.8 to 2 m2 and represents our interface with the environment; however, when one considers that microorganisms live in the hair follicles and can enter sweat ducts, the area that interacts with this aspect of the environment becomes about 25-30 m2. Although all layers of the skin, including the adipose tissue, participate in antimicrobial defense, this review will focus mainly on the role of the antimicrobial factors in the epidermis and at the skin surface. The outermost layer of the epidermis, the stratum corneum, is physically tough and chemically inert which protects against numerous environmental stresses. It provides a permeability barrier which is attributable to lipids in the intercellular spaces between the corneocytes. In addition to the permeability barrier, there is an innate antimicrobial barrier at the skin surface which involves antimicrobial lipids, peptides and proteins. The skin surface has a low surface pH and is poor in certain nutrients, which limits the range of microorganisms that can survive there. Melanin and trans-urocanic acid provide protection from UV radiation, and Langerhans cells in the epidermis are poised to monitor the local environment and to trigger an immune response as needed. Each of these protective barriers will be discussed.

Lipid Metabolic Events Underlying the Formation of the Corneocyte Lipid Envelope.

Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the lamellar granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the lamellar granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff's base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of lamellar granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.

Roles of Lipids in the Permeability Barriers of Skin and Oral Mucosa.

PubMed searches reveal much literature regarding lipids in barrier function of skin and less literature on lipids in barrier function of the oral mucosa. In terrestrial mammals, birds, and reptiles, the skin's permeability barrier is provided by ceramides, fatty acids, and cholesterol in the outermost layers of the epidermis, the stratum corneum. This layer consists of about 10-20 layers of cornified cells embedded in a lipid matrix. It effectively prevents loss of water and electrolytes from the underlying tissue, and it limits the penetration of potentially harmful substances from the environment. In the oral cavity, the regions of the gingiva and hard palate are covered by keratinized epithelia that much resemble the epidermis. The oral stratum corneum contains a lipid mixture similar to that in the epidermal stratum corneum but in lower amounts and is accordingly more permeable. The superficial regions of the nonkeratinized oral epithelia also provide a permeability barrier. These epithelial regions do contain ceramides, cholesterol, and free fatty acids, which may underlie barrier function. The oral epithelial permeability barriers primarily protect the underlying tissue by preventing the penetration of potentially toxic substances, including microbial products. Transdermal drug delivery, buccal absorption, and lipid-related disease are discussed.

Synopsis of Barrier Function of Skin and Oral Mucosa-Volume 1.

This is an attempt to make readers of the second edition of International Journal of Molecular Sciences Special Issue on the Barrier Function of Skin and Oral Mucosa aware of the content of the first edition on this same topic [...].

Protein Analysis of Sapienic Acid-Treated Porphyromonas gingivalis Suggests Differential Regulation of Multiple Metabolic Pathways.

UNLABELLED: Lipids endogenous to skin and mucosal surfaces exhibit potent antimicrobial activity against Porphyromonas gingivalis, an important colonizer of the oral cavity implicated in periodontitis. Our previous work demonstrated the antimicrobial activity of the fatty acid sapienic acid (C(16:1Δ6)) against P. gingivalis and found that sapienic acid treatment alters both protein and lipid composition from those in controls. In this study, we further examined whole-cell protein differences between sapienic acid-treated bacteria and untreated controls, and we utilized open-source functional association and annotation programs to explore potential mechanisms for the antimicrobial activity of sapienic acid. Our analyses indicated that sapienic acid treatment induces a unique stress response in P. gingivalis resulting in differential expression of proteins involved in a variety of metabolic pathways. This network of differentially regulated proteins was enriched in protein-protein interactions (P = 2.98 × 10(-8)), including six KEGG pathways (P value ranges, 2.30 × 10(-5) to 0.05) and four Gene Ontology (GO) molecular functions (P value ranges, 0.02 to 0.04), with multiple suggestive enriched relationships in KEGG pathways and GO molecular functions. Upregulated metabolic pathways suggest increases in energy production, lipid metabolism, iron acquisition and processing, and respiration. Combined with a suggested preferential metabolism of serine, which is necessary for fatty acid biosynthesis, these data support our previous findings that the site of sapienic acid antimicrobial activity is likely at the bacterial membrane. IMPORTANCE: P. gingivalis is an important opportunistic pathogen implicated in periodontitis. Affecting nearly 50% of the population, periodontitis is treatable, but the resulting damage is irreversible and eventually progresses to tooth loss. There is a great need for natural products that can be used to treat and/or prevent the overgrowth of periodontal pathogens and increase oral health. Sapienic acid is endogenous to the oral cavity and is a potent antimicrobial agent, suggesting a potential therapeutic or prophylactic use for this fatty acid. This study examines the effects of sapienic acid treatment on P. gingivalis and highlights the membrane as the likely site of antimicrobial activity.

Time Course of Potassium Nitrate Penetration into the Pulp Cavity and the Effect of Penetration Levels on Tooth Whitening Efficacy.

OBJECTIVES: To establish time-course of potassium nitrate (PN) penetration into the pulp cavity, and determine whether PN pretreatment would affect whitening efficacy. MATERIALS AND METHODS: Extracted teeth (n = 100) were randomized into five groups of 20 specimens each. Relief ACP (Philips Oral Healthcare, Los Angeles, CA, USA) was applied for 0, 5, 15, 30, and 60 minutes for groups 15, respectively. A nitrate/nitrite assay kit was used for colorimetric detection of nitrate. Whitening was performed using a Zoom White Speed system (Philips Oral Healthcare) for 60 minutes. Tooth color was measured with a spectrophotometer at baseline (T0 ), 1-day post PN application (T1 ), 1-day post-whitening (T2 ), and 1-month post-whitening (T3 ). Kruskal-Wallis test was used to assess group differences in PN penetration and tooth color change. RESULTS: PN penetration differed among all groups except 2 and 3. There were no differences among groups for any baseline color parameters (p > 0.30). At T2 there was no change relative to baseline for individual components L*, a*, and b*. At T3 and T4 there was significant change relative to baseline for ΔL*, Δb*, and ΔE*, for all groups. CONCLUSIONS: PN penetration is time dependent and pretreatment with PN does not affect whitening efficacy. CLINICAL SIGNIFICANCE: Postassium nitrate penetration into the pulp cavity occurred as early as 5 minutes after application, and pretreatment with potassium nitrate containing desensitizers did not adversely affect tooth whitening efficacy. (J Esthet Restor Dent 28:S14-S22, 2016).

The Effect of Delivery System and Light Activation on Tooth Whitening Efficacy and Hydrogen Peroxide Penetration.

PURPOSE: To evaluate the whitening efficacy of a new two-layer technology in-office system compared to a conventional gel-type system and determine hydrogen peroxide penetration (HPP) into the pulp cavity. MATERIALS AND METHODS: Extracted molars (n = 60) were assigned to group NC: glycerol gel; group QPRO: 20% HP varnish (Zoom Quick Pro, Philips Oral Healthcare); group ZOOM_NL: 25% HP gel (Zoom Chairside Whitening); and group ZOOM_WL: 25% HP gel (Zoom Chairside Whitening) with light-activation. HPP levels were estimated with leucocrystal-violet and horseradish-peroxidase. Instrumental color measurements were performed at baseline (T0 ), 1-day post first whitening (T1 ), 1-day post second whitening (T2 ), 1-day post third whitening (T3 ), and 1-month post whitening (T4 ). One-way analysis of variance followed by post hoc Tukey's HSD test was performed to detect difference in ΔE* and HP penetration levels (α = 0.05). RESULTS: ΔE* of NC was lower than other groups, whereas ΔE* of ZOOM_WL was greater than the other three groups, at T3 and T4 . Mean HPP level obtained from ZOOM_WL (1.568 ± 0.753 µg/mL) was significantly greater than those obtained from the other groups, whereas the mean HPP level observed in NC group (-0.131 ± 0.003 µg/mL) was significantly lower than the other groups. CONCLUSIONS: Tooth whitening efficacy and HPP levels vary based on whitening systems used. CLINICAL SIGNIFICANCE: The two-layer technology in-office varnish system may be an alternative whitening option to reduce chair time in the office. (J Esthet Restor Dent 28:313-320, 2016).

The roles of cutaneous lipids in host defense.

Lauric acid (C12:0) and sapienic acid (C16:1Δ6) derived from human sebaceous triglycerides are potent antimicrobials found at the human skin surface. Long-chain bases (sphingosine, dihydrosphingosine and 6-hydroxysphingosine) are also potent and broad-acting antimicrobials normally present at the skin surface. These antimicrobials are generated through the action of ceramidases on ceramides from the stratum corneum. These natural antimicrobials are thought to be part of the innate immune system of the skin. Exogenously providing these lipids to the skin may provide a new therapeutic option, or could potentially provide prophylaxis in people at risk of infection. This article is part of a Special Issue entitled The Important Role of Lipids in the Epidermis and their Role in the Formation and Maintenance of the Cutaneous Barrier. Guest Editors: Kenneth R. Feingold and Peter Elias.

Review of the Mechanism of Tooth Whitening.

PURPOSE: This review integrated the current literature on diffusion of whitening agents, their interactions with stain molecules, and changes to the surface, with the aim of establishing a better understanding of the mechanism underlying tooth whitening. MATERIALS AND METHODS: An electronic PubMed database search, with combinations of the following terms was performed: Tooth Bleaching, Tooth Bleaching Agent, Hydrogen Peroxide, Pharmacokinetics, Tooth Permeability, Oxidation-Reduction, Tooth Demineralization, and Color. RESULTS: Tooth whitening is a dynamic process that involves diffusion of the whitening material to interact with stain molecules and also involves micromorphologic alterations on the surface and changes within the tooth that affect its optical properties. The interaction seems not to be limited to stain molecules, but rather an affinity-based interaction process that also accompanies effects on sound enamel and dentin structures. CONCLUSIONS: This review underlines that supervision by dental health professionals as recommended by the American Dental Association (ADA) Council on Scientific Affairs is critical to achieving a successful and safe whitening outcome. CLINICAL SIGNIFICANCE: The mechanism that underlies tooth whitening with the use of peroxide-based materials is a complex phenomenon encompassing diffusion, interaction, and surfaces changes within the tooth. Therefore, supervision by dental health professionals as recommended by the ADA Council on Scientific Affairs is imperative to achieve a successful and safe whitening outcome.

Antibacterial activity of sphingoid bases and fatty acids against Gram-positive and Gram-negative bacteria.

There is growing evidence that the role of lipids in innate immunity is more important than previously realized. How lipids interact with bacteria to achieve a level of protection, however, is still poorly understood. To begin to address the mechanisms of antibacterial activity, we determined MICs and minimum bactericidal concentrations (MBCs) of lipids common to the skin and oral cavity--the sphingoid bases D-sphingosine, phytosphingosine, and dihydrosphingosine and the fatty acids sapienic acid and lauric acid--against four Gram-negative bacteria and seven Gram-positive bacteria. Exact Kruskal-Wallis tests of these values showed differences among lipid treatments (P < 0.0001) for each bacterial species except Serratia marcescens and Pseudomonas aeruginosa. D-sphingosine (MBC range, 0.3 to 19.6 µg/ml), dihydrosphingosine (MBC range, 0.6 to 39.1 µg/ml), and phytosphingosine (MBC range, 3.3 to 62.5 µg/ml) were active against all bacteria except S. marcescens and P. aeruginosa (MBC > 500 µg/ml). Sapienic acid (MBC range, 31.3 to 375.0 µg/ml) was active against Streptococcus sanguinis, Streptococcus mitis, and Fusobacterium nucleatum but not active against Escherichia coli, Staphylococcus aureus, S. marcescens, P. aeruginosa, Corynebacterium bovis, Corynebacterium striatum, and Corynebacterium jeikeium (MBC > 500 µg/ml). Lauric acid (MBC range, 6.8 to 375.0 µg/ml) was active against all bacteria except E. coli, S. marcescens, and P. aeruginosa (MBC > 500 µg/ml). Complete killing was achieved as early as 0.5 h for some lipids but took as long as 24 h for others. Hence, sphingoid bases and fatty acids have different antibacterial activities and may have potential for prophylactic or therapeutic intervention in infection.

Effects of golden tomato extract on skin appearance-outlook into gene expression in cultured dermal fibroblasts and on trans-epidermal water loss and skin barrier in human subjects.

SCOPE: Two experiments were performed to test the effects of rich tomato extract (Golden Tomato Extract, GTE) on human skin. In one experiment, the effects of this extract on gene expression in cultured human dermal fibroblasts were examined. In a second experiment, human subjects consumed the extract and trans-epidermal water loss (TEWL), and aspects of skin appearance were monitored. METHODS AND RESULTS: Primary human dermal fibroblasts in culture were treated with the extract. After six hours, RNA was extracted, and gene expression was examined using Affymetrix Human Clariom D array processing. For the clinical study, 65 human subjects consumed a capsule once a day for 16 weeks, and various skin parameters were assessed at predetermined time intervals. Among the genes upregulated by GTE are genes that augment innate immunity, enhance DNA repair, and the ability to detoxify xenobiotics. GTE significantly reduced TEWL in subjects who had high TEWL at baseline, but it had no effect on TEWL in subjects who had lower TEWL at baseline. CONCLUSIONS: Golden tomato extract may provide benefits to the skin by enhancing innate immunity and other defense mechanisms in the dermis and by providing antioxidants to the skin surface to optimize TEWL and the appearance of the skin.

Lipid defect underlies selective skin barrier impairment of an epidermal-specific deletion of Gata-3.

Skin lies at the interface between the complex physiology of the body and the external environment. This essential epidermal barrier, composed of cornified proteins encased in lipids, prevents both water loss and entry of infectious or toxic substances. We uncover that the transcription factor GATA-3 is required to establish the epidermal barrier and survive in the ex utero environment. Analysis of Gata-3 mutant transcriptional profiles at three critical developmental stages identifies a specific defect in lipid biosynthesis and a delay in differentiation. Genomic analysis identifies highly conserved GATA-3 binding sites bound in vivo by GATA-3 in the first intron of the lipid acyltransferase gene AGPAT5. Skin from both Gata-3-/- and previously characterized barrier-deficient Kruppel-like factor 4-/- newborns up-regulate antimicrobial peptides, effectors of innate immunity. Comparison of these animal models illustrates how impairment of the skin barrier by two genetically distinct mechanisms leads to innate immune responses, as observed in the common human skin disorders psoriasis and atopic dermatitis.

Effect of menthol on the penetration of tobacco carcinogens and nicotine across porcine oral mucosa ex vivo.

INTRODUCTION: Menthol is a flavored tobacco additive claimed to mask the bitter taste and reduce the harshness of cigarette smoke. (Azzi, C., Zhang, J., Purdon, C. H., Chapman, J. M., Nitcheva, D., Hebert, J. R., et al., 2006, Permeation and reservoir function of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (B[a]P) across porcine esophageal tissue in the presence of ethanol and menthol. Carcinogenesis, 27, 137-145). have shown that menthol increased the flux of tobacco carcinogens (TC) across porcine esophagus. As oral mucosa is exposed to both smoke and smokeless tobacco in tobacco users, the objective of this study was to determine whether menthol influenced the penetration of the TC nitrosonornicotine (NNN) across porcine buccal (BM) and floor of mouth (FM) mucosa. METHODS: Porcine BM and FM were collected at slaughter, mounted in perfusion chambers (n = 7/group), and exposed to tritiated NNN ((3)H-NNN; Amersham, activity 1 muCi/ml) and tritiated nicotine ((3)H-nicotine; Sigma) in 3% nicotine/phosphate-buffered saline (0.01 M, pH 7.4) containing 0.01% unlabeled NNN (National Cancer Institute Chemical Carcinogen Repository) +/- 0.08% menthol for 0.5, 1, 2, or 12 hr. K(p) values (cm/min) were determined and statistically analyzed (analysis of variance, Tukey's, p < .05). RESULTS: FM and BM permeability to both (3)H-NNN and (3)H-nicotine was significantly increased (p < .05) with addition of menthol over that of nicotine alone regardless of exposure times. Even short 30-min menthol exposure significantly increased the flux of both compounds, and this was maintained throughout the experiment. DISCUSSION: Menthol enhances penetration of NNN and nicotine through FM and BM in vitro, even after short exposure. This may reflect loading of a superficial epithelial reservoir (Squier, C. A., Kremer, M. J., Bruskin, A., Rose, A., & Haley, J. D., 1999. Oral mucosal permeability and stability of transforming growth factor beta-3 in vitro. Pharmaceutical Research, 16, 1557-1563.), thus delivering menthol and enhancing flux for several hours. Practical implications are for a potentially increased oral exposure to carcinogens among users of menthol-flavored cigarettes and chewing tobacco.

Formulation and stability of a novel artificial sebum under conditions of storage and use.

Materials in contact with liquids on the human skin surface may dissolve and permeate into skin. Release and permeation of chemicals in contact with skin is often estimated in vitro using artificial skin liquids, although sebum lipids are generally not included in these models. The purposes of this research were to develop a representative artificial sebum that contains the appropriate types of lipids at levels that match human values and quantitatively characterize the model to understand its utility for in vitro testing. Artificial sebum that consisted of 10 lipids at proportions that closely resembled human sebum was characterized using thin layer chromatography under a variety of storage and use conditions (dry and liquid, 4°C and 32°C, with and without vitamin E) for 28 days. Levels of sebum constituents maintained in solution and dry at 4°C were stable through the duration of the test period. Levels of all sebum lipids maintained dry at 32°C were stable in the presence of vitamin E; however, squalene oxidized rapidly in the absence of vitamin E. Liquids on the human skin surface consist of sebum and sweat with minor amounts of cellular debris and intercellular lipid from the stratum corneum. The relative importance of each component for release of chemicals from materials in contact with skin will depend upon the type of material (metal, organic, etc.). A model artificial sebum was formulated and characterized to aid researchers in understanding potential release of chemicals from materials in contact with skin and subsequent partitioning and absorption.

Innate Antimicrobial Defense of Skin and Oral Mucosa.

This special issue intends to review and update our understanding of the antimicrobial defense mechanisms of the skin and oral cavity. These two environments are quite different in terms of water, pH, and nutrient availability, but have some common antimicrobial factors. The skin surface supports the growth of a limited range of microorganisms but provides a hostile environment for others. The growth of most microorganisms is prevented or limited by the low pH, scarcity of some nutrients such as phosphorus and the presence of antimicrobial peptides, including defensins and cathelicidins, and antimicrobial lipids, including certain fatty acids and long-chain bases. On the other hand, the oral cavity is a warm, moist, nutrient rich environment which supports the growth of diverse microflora. Saliva coating the oral soft and hard surfaces determines which microorganisms can adhere to these surfaces. Some salivary proteins bind to bacteria and prevent their attachment to surfaces. Other salivary peptides, including defensins, cathelicidins, and histatins are antimicrobial. Antimicrobial salivary proteins include lysozyme, lactoferrin, and lactoperoxidase. There are also antimicrobial fatty acids derived from salivary triglycerides and long-chain bases derived from oral epithelial sphingolipids. The various antimicrobial factors determine the microbiomes of the skin surface and the oral cavity. Alterations of these factors can result in colonization by opportunistic pathogens, and this may lead to infection. Neutrophils and lymphocytes in the connective tissue of skin and mucosa also contribute to innate immunity.

Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1.

Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH2-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1-deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH2-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation.

Characterization and quantification of ceramides in the nonlesional skin of canine patients with atopic dermatitis compared with controls.

As in humans, there is mounting evidence in support of an abnormal skin barrier contributing to the pathogenesis of canine atopic dermatitis (AD). Studies in people with AD have associated an abnormal skin barrier with deficiencies in ceramides, which represent important components of the stratum corneum (SC) intercellular lipid lamellae. Therefore, the goal of this study was to determine if the SC of dogs with AD is deficient in ceramides compared to normal dogs. Samples of SC were obtained from nonlesional skin of the caudal abdomen of 14 patients with AD and 14 age-, breed- and sex-matched healthy controls using a cyanoacrylate stripping procedure, and the subclass and relative amount of ceramides were assessed blindly by thin layer chromatography. Paired t-tests using R statistical computer software revealed the percentage amounts of ceramides 1 and 9 were significantly lower in nonlesional skin of AD dogs compared to controls (P= 0.034 and P= 0.047, respectively), and the cholesterol percentage amount was significantly higher in AD dogs than in controls (P= 0.016). Furthermore, the cholesterol/ceramide ratio was significantly higher in the AD group with respect to controls (P= 0.014). These findings suggest that decreased amounts of ceramides in the skin of dogs with AD may be involved in the impaired barrier function of their skin.

Lipids and the Permeability and Antimicrobial Barriers of the Skin.

The primary purpose of the epidermis of terrestrial vertebrates is to produce the stratum corneum, which serves as the interface between the organism and the environment. As such, the stratum corneum provides a permeability barrier which both limits water loss through the skin and provides a relatively tough permeability barrier. This provides for a degree of resistance to mechanical trauma and prevents or limits penetration of potentially harmful substances from the environment. The stratum corneum consists of an array of keratinized cells embedded in a lipid matrix. It is this intercellular lipid that determines the permeability of the stratum corneum. The main lipids here are ceramides, cholesterol, and fatty acids. In addition, the skin surface of mammals, including humans, is coated by a lipid film produced by sebaceous glands in the dermis and secreted through the follicles. Human sebum consists mainly of squalene, wax monoesters, and triglycerides with small proportions of cholesterol and cholesterol esters. As sebum passes through the follicles, some of the triglycerides are hydrolyzed by bacteria to liberate free fatty acids. Likewise, near the skin surface, where water becomes available, some of the ceramides are acted upon by an epithelial ceramidase to liberate sphingosine, dihydrosphingosine, and 6-hydroxysphingosine. Some of the free fatty acids, specifically lauric acid and sapienic acid, have been shown to have antibacterial, antifungal, and antiviral activity. Also, the long-chain bases have broad spectrum antibacterial activity.