Disorders of skin barriers: clinical implications.

Abstract

Stratum corneum barrier is generally described according to the ‘brick and mortar’ model, which consists of corneocytes and intercellular lipids. Corneocytes are composed mainly of insoluble bundled keratins surrounded by a cell envelope stabilized by cross-linked proteins and covalently bound lipids. Polar structures, such as corneodesmosomes, interconnect corneocytes thus contributing to stratum corneum cohesion. Intercellular lipids are primarily generated from exocytosis of lamellar bodies during the terminal differentiation of keratinocytes, and less importantly are generated by sebaceous output. Intercellular lipids are required for a competent skin barrier and homeostatic control of transcutaneous penetration.1 The stratum corneum barrier is a dynamic structure resulting from the processes of cornification and desquamation that are intimately linked; the control of its formation in response to barrier perturbation is directly relevant to the aetiology of several skin diseases as well to the development of new strategies for skin treatment and barrier fortification. The synthesis of corneocytes requires a period of between 2 and 4 weeks where keratin filaments undergo a process of maturation as revealed by the expression of different markers; indeed, keratin K5 and K4 synthesis occurring in the basal layer is replaced by K1 and K10 in the suprabasal region. Furthermore, changes in keratin expression can be influenced by calcium concentration, epidermal growth factors and drugs, such as retinoids. In the granular layer, keratins are bundled with microfibrils, such as filaggrin and its precursor, profilaggrin. Profilaggrin synthesis is enhanced by calcium in vitro and decreased by retinoic acid. Filaggrin is degraded into the stratum corneum in amino acids, pyrrolidone carboxylic acid and urocanic acid: all these factors can influence stratum corneum hydration and water holding capacity. Indeed, a decrease in environmental humidity downregulates filaggrin expression in the keratinocytes via oxidative stress, thus reducing amino acids in the stratum corneum and consequently causing skin dryness. Premature bundling of intermediate filaments associated with an increased susceptibility to cytolysis can be the triggering factor in several congenital skin diseases, such as bullous congenital ichthyosiform erythroderma and epidermolytic palmoplantar keratosis: in both these genodermatoses the granular layer is thickened and the formation of keratohyalin granules occur very early. The segregation of cytoplasmic constituents after keratin clumping results in loss of stability and cytolysis occurs under mechanical stress and trauma. In epidermolysis bullosa herpetiformis Dowling–Meara the same structural changes have been reported, but limited to the basal layer. An increase in filaggrin has been described in these disorders and correlations between the structural abnormalities of keratin filaments and filaggrin have been postulated but not confirmed.2 Other factors can influence the assembly and organization of corneocytes into the stratum corneum, such as involucrin and loricrin, amino-acid-rich molecules, and the enzymes transglutaminases important for the formation of the cornified envelopes.3 Lipids are covalently attached to the cornified envelopes: these are mainly ceramides derived from glucosylceramides present in lamellar bodies. The role of these covalently bound lipids has been hypothesized to be relevant for stratum corneum cohesion, for the organization of the intercellular lipid and for the permeability properties of the corneocytes. In psoriasis, the amount of these covalently bound lipids is the same as in normal subjects, but the level of ceramide 2 is reduced, whereas the level of free fatty acids and ω-hydroxyacids is increased. A defective maturation of the cornified envelope may account for impairment of barrier function in some inflammatory skin disorders: immature cornified envelopes are present in psoriasis and atopic dermatitis and are often associated with parakeratosis. Intercellular lipids play a major part in maintaining and modulating barrier efficiency: the process required for the formation of the structures of the intercellular spaces goes from the synthesis of precursor lipids in keratinocytes, assembly of these lipids into lamellar bodies and exocytosis of the lamellar bodies with processing of these lipids to organize lamellar structures in the intercellular spaces of the stratum corneum. Cholesterol, ceramides, and essential and non-essential fatty acids play a key part in the formation of these bilayers. Stratum corneum lipids are composed of about 40% ceramides, 25% cholesterol and 20% free fatty acids (by weight).4 Taking the average molecular weight of these three lipid classes into account, the normal stratum corneum has an approximately equimolar physiological ratio of ceramides, cholesterol and free fatty acids. Following barrier disruption in hairless mice, epidermal cholesterol and fatty acid syntheses is immediately increased, while increased ceramide production is evident about 6 h later.5 These key barrier lipids are delivered to the intercellular space of the stratum corneum as a mixture of precursors by the extrusion of lamellar body content at the stratum granulosum–stratum corneum interface.6,7 Fusion of the extruded lamellar contents within the lower stratum corneum leads to continuous membrane sheets, which ultimately form mature membrane bilayer structures.6 The final membrane structural transformation correlates with changes in lipid composition; i.e. the polar lipid precursors (glycosphingolipids, phospholipids and cholesterol sulphate) are metabolized to more non-polar lipid products.5,7 Atopic dermatitis is characterized by impaired barrier function, increased transepidermal water loss and stratum corneum xerosis resulting from reduced levels of ceramides in the intercellular lipid domain.8 Irritant contact dermatitis can easily generate on a disrupted barrier, due both to enhanced transcutaneous penetration of aggressive chemicals and to xerosis and desquamation as a consequence of increased water loss from the skin surface. In this light, irritant contact dermatitis can be seen as a preliminary step towards the development of permanent sensitization. Potentially harmful sensitizers can have easy access to living epidermal structures in irritated skin leading to permanent sensitization and skin damage. Atopic eczema is an important clinical model to understand how defective barrier function can lead to the development of inflammatory skin disease. Indeed, antigens and/or superantigens released by microbial flora can easily penetrate a deranged barrier and act as potent immunostimulatory molecules capable of activating up to 20% of all T cells thus producing interleukin-4 and stimulating B cells to produce IgE. This can result in the formation of eczematous lesions and a dermal inflammatory reaction. Studies have shown how experimentally induced stratum corneum damage by stripping can induce interleukin-1α, interleukin-1β and tumour necrosis factor-α expression, initiating a cytokine cascade that could regulate cytokine and cytokine receptor production and/or inflammatory responses.9 Therefore, this shows how a complex inflammatory reaction involving immunological responses can be initiated only by external stimuli induced and mediated by stratum corneum damage.10 These exciting studies open up new perspectives in the therapeutic approaches of eczematous conditions as well as contact dermatitis. Indeed, topical application of physiological lipids has distinct effects from those of non-physiological lipids, such as petrolatum. For example, studies have shown that topical application of only one or two of the three physiological lipids to a disrupted hairless mouse skin impedes rather than facilitates barrier recovery, evidenced by changes in transepidermal water loss.11 However, if members of all three key lipid classes (i.e. cholesterol, ceramide and free fatty acids or their precursors) are applied together to barrier-disrupted skin, normalized rates of barrier repair are observed.11 The topically applied physiological lipids are not only concentrated in the stratum corneum membrane domains, but also are delivered to the nucleated layers of the epidermis. Depending on the composition of the lipid mixture, either normal or abnormal lamellar bodies are formed, ultimately resulting in either normal or abnormal lamellar membrane unit structures in the stratum corneum intercellular spaces.11,12 It appears that the incorporation of applied physiological lipids into barrier lipids follows two pathways: (i) direct incorporation into stratum corneum membrane domains, and (ii) lipids appear to traverse the intercellular route in the stratum corneum, and ultimately become incorporated into lower stratum granulosum cells. The intercellular lipids then appear able to enter the nucleated cells, incorporate into the appropriate lipid metabolic pathway(s) and ultimately utilize the lamellar body delivery system to re-enter the intercellular membrane domains. Topically applied lipids to either intact or acetone-treated skin did not downregulate the physiological lipid synthesis. These studies support the hypothesis that the epidermis can internalize and process physiological lipids. In contrast, non-physiological lipids, such as petrolatum appear to form simply a bulk hydrophobic phase in the stratum corneum intercellular spaces to restore the barrier under similar conditions.12 The same studies showed further enhancement of barrier recovery if the proportion of one of the fatty acids (linoleic acid, palmitic acid or stearic acid) or the other key species was augmented to threefold in a four-component system, i.e. consisting of fatty acids, ceramides, cholesterol, essential fatty acids in a 3 : 1 : 1 : 1 ratio. Interestingly, acylceramides applied as a single agent delayed barrier recovery. However, acylceramides in a mixture with cholesterol (optimum ratio of 1.5 : 1 or 1 : 2, respectively) also revealed accelerated barrier recovery after acute barrier disruption. Stratum corneum hydration (measured by conductance) is increased 4 h after topical application of cholesterol, acylceramide, petrolatum and glycerol containing vehicle (propylene glycol/ethanol) and also accelerated barrier repair was noted using a similar formulation after tape stripping, solvent treatment and some types of detergent treatment. However, it must be noted, that in barrier repair vs. hydration studies, correlations between moisturizing properties and barrier repair mechanism of applied lipid mixtures are not always evident. Actually, the best hydrating lipid composition is often different from the optimal barrier repair formulation and vice versa.13,14 In the light of these findings, it appears clear that any therapeutic approach that restores stratum corneum barrier function not only can improve the ‘cosmetic’ appearance of the skin, but can treat the skin as well, by reducing transcutaneous penetration of sensitizers and chemicals and decrease the release of proinflammatory mediators induced by a disrupted barrier. Furthermore, in particular conditions, such as atopic eczema, the restoring of a functional barrier can prevent the interaction of superantigens with an abnormal immune system and thereby prevent the development of eczematous lesions.