Skin barrier function, epidermal proliferation and differentiation in eczema

Skin permeability barrier function is impaired in eczema, particularly in contact and atopic dermatitis (AD). In contact dermatitis disruption of the barrier by irritants and allergens is the primary event, followed by sensitization, inflammation, increased epidermal proliferation and changes in differentiation. Genetically impaired skin barrier function is already present in non-lesional and more pronounced in lesional skin in AD. Increased epidermal proliferation and disturbed differentiation, including changes in lipid composition, cause impaired barrier function in AD. Defective permeability barrier function enables the enhanced penetration of environmental allergens into the skin and initiates immunological reactions and inflammation. Barrier dysfunction is therefore crucially involved in the pathogenesis of AD. The atopic syndrome represents a genetically impaired skin barrier function as well as impaired nasal, bronchial, and intestinal mucous membranes leading to AD, allergic rhinitis, bronchial asthma or aggravation of AD. Common treatment strategies for eczema include the application of lipid-based creams and ointments, which aim toward the restoration of the defective permeability barrier, thus helping to normalize proliferation and differentiation.     

Augmentation of skin response by exposure to a combination of allergens and irritants - a review

Clinical experimental studies on contact dermatitis (CD) often evaluate the effect of one allergen or one irritant at a time. In real life, the skin is often exposed to more allergens, more irritants or allergens and irritants in combination. This combined exposure may potentially influence irritant effects as well as allergenicity of the substances. Mechanisms for a changed response can be immunological effects or enhanced penetration. Knowledge about the influence on skin reaction of combined exposures may influence skin reactivity and is important for prevention of CD. For allergens, threshold values may be influenced by the presence of other allergens or irritants, and prevention of CD by regulation of threshold values may not be sufficient if this is not taken into account.     

Murine auricular transepidermal water loss -- a novel approach for evaluating irritant skin reaction in mice

The standard method for evaluating contact allergy in mice is the ear swelling technique. However, in experimental irritant contact dermatitis, the epidermal barrier disruption, that represents a predominant effect of irritants, cannot be assayed by this METHOD: An appropriate method to evaluate barrier disruption is the measurement of transepidermal water loss (TEWL) but to date this has so far been possible only on the trunk of hairless or shaved mice. We therefore developed a new technique to measure the TEWL of mice ears (murine auricular TEWL: MATEWL). After patch testing with irritants and allergens, respectively, we found that the ear swelling method is most suitable for evaluating allergic skin reactions, whereas MATEWL is most appropriate for evaluating irritant skin reactions.     

Role of the epidermal barrier in atopic dermatitis

The skin's permeability barrier protects against extensive water loss and prevents the entry into the skin of harmful substances like irritants, allergens and microorganisms. The permeability barrier is mainly located in the stratum corneum and consists of corneocytes and a lipid‐enriched intercellular domain. The barrier is formed during epidermal differentiation. In atopic dermatitis the skin barrier is disturbed already in non‐lesional skin. The disturbed skin barrier allows the entry of environmental allergens from house dust mites, animal dander and grass pollen into the skin. In predisposed individuals these allergens may trigger via immunologic pathways the inflammation of atopy. The causes for the disturbed epidermal skin barrier are changes in skin lipids and in epidermal differentiation, in particular filaggrin mutations. Filaggrin mutations lead to a disturbed skin barrier and dry skin which are hallmarks in atopic dermatitis. Therapeutic agents influence the skin barrier differently; topical therapy with potent corticosteroids does not lead to the repair of the barrier in atopic dermatitis, whereas therapy with the calcineurin inhibitors and lipid‐containing emulsions support barrier repair.     

Contact Dermatitis in Older Adults

Contact dermatitis is a significant health problem affecting the elderly. Impaired epidermal barrier function and delayed cutaneous recovery after insult enhances susceptibility to both irritants and allergens. Exposure to more numerous potential sensitizers and for greater durations influences the rate of allergic contact dermatitis in this population.Medical co-morbidities, including stasis dermatitis and venous ulcerations, further exacerbate this clinical picture. However, while these factors tend to increase the degree of sensitization in the elderly, waning immunity can actually decrease such a propensity. This interplay of both intrinsic and extrinsic factors makes a generalization on trends for contact dermatitis in older adults challenging. The literature has varying reports on the overall incidence of allergic contact dermatitis with advancing age. Nevertheless, it does clearly show that sensitivity to topical medicaments increases with age. Irritant contact dermatitis studies are more consistent, with less reactivity (to irritants) in older compared with younger skin. Diagnosis of both irritant and allergic contact dermatitis is based on a thorough history, complete skin examination, and comprehensive patch testing. The mainstay of therapy is avoidance of the offending chemical substances and the use of topical along with systemic therapies, depending on the severity of the condition.     

Contact dermatitis

Contact dermatitis is a common skin disease caused by contact with irritants or allergens. Irritant contact dermatitis is a result of nonspecific irritant factors, which cause activation of mainly innate immunity, resulting in skin inflammation. Contact hypersensitivity, which manifests itself as allergic contact dermatitis, is result of adaptive immune response, where sensitization to hapten-carrier complexes leads to T-cell-mediated contact allergy. Subsequent contact with the hapten results in skin inflammation. This review concentrates on the role of cutaneous receptors in contact dermatitis and highlights potential targets for treatment interventions.     

Dry skin, barrier function, and irritant contact dermatitis in the elderly

Dry skin is characterized by a decreased lipid content and a delayed reconstitution of the epidermal barrier after skin irritation. These are problems of high relevance in the aged population, especially in the development of irritant contact dermatitis. Asteatotic and perineal irritant dermatitis are the most important subtypes of irritant contact dermatitis in the elderly. This contribution presents a compressed survey on these subtypes and elucidates their relation to an impaired barrier function. Typical irritants affecting aged individuals are explained and compared with irritants that seem to be more significant in younger people. Results of biophysical investigations, such as measurement of transepidermal water loss, are discussed regarding their age-dependence. Transepidermal water loss decreases with age, which was formerly interpreted as an indication of a decreased sensitivity. Today, we know that reconstitution of the epidermal barrier after irritation is delayed once it has been impaired. Reasons are decreased activities of enzymes involved in lipid synthesis and processing, a changed cytokine profile, a reduced acidification of aged skin, and alterations in the function of epidermal stem cells. Owing to these new insights, a reevaluation of the sensitivity of aged skin has to be initiated, especially with regard to occupational dermatology.     

Skin reactions to irritants assessed by non-invasive bioengineering methods

Pathophysiological components of irritant contact dermatitis caused by 3 chemically-different irritants were investigated. 20 healthy volunteers were patch tested with sodium lauryl sulphate, nonanoic acid and hydrochloric acid on the flexor side of the upper arm. The skin response was evaluated after 24, 48 and 96 h by visual scoring and measured by the following bioengineering methods: transepidermal water loss measurement, electrical conductance for measurement of skin hydration, laser Doppler flowmetry for measurement of cutaneous blood flow and 20 MHz ultrasound A-scan for measurement of skin thickness. In spite of homogeneous inflammatory responses, significant differences in the severity of the injury to the skin barrier function caused by the different irritants were found. Also significant differences between irritants were found in the time course of development of maximum irritant reactions. Bioengineering methods indicating inflammatory responses (measurement of blood flow and skin thickness) were helpful in quantifying the irritant response in general, while bioengineering methods indicating epidermal damage (measurement of TEWL and electrical conductance) were helpful in classifying the individual irritants.     

Loss-of-function mutations in the filaggrin gene and allergic contact sensitization to nickel

Allergic contact dermatitis is one of the most frequent dermatological problems affecting 7% of the general population. Impaired skin barrier function facilitates the penetration of contact allergens and irritants into the epidermal layer and is regarded as an important cofactor promoting the process of allergic contact sensitization. Filaggrin is crucial for the maintenance of the skin barrier function. Loss-of-function mutations within the filaggrin (FLG) gene are associated with skin barrier diseases such as ichthyosis vulgaris and atopic eczema (AE). To assess the impact of FLG on allergic contact sensitization and plausible intermediate traits, the two prevalent FLG mutations R501X and 2282del4 were typed in 1,502 individuals of the KORA C population-based cohort with extensive dermatologic phenotyping. Associations of FLG mutations with AE could be replicated. Strong associations were seen with dry skin, palmar hyperlinearity, and keratosis pilaris. In addition, an association with contact sensitization to nickel and contact sensitization to nickel combined with intolerance to fashion jewelry, but not with other contact allergens, was observed. From these data, we conclude that a genetically determined FLG deficiency manifests as dry skin and features of ichthyosis vulgaris. In addition, FLG deficiency may also represent a risk factor for contact sensitization to allergens.     

Impaired sphingomyelinase activity and epidermal differentiation in atopic dermatitis

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.     

Epidemiology of occupational skin disease in Singapore 1989-1998

This is an epidemiologic study of occupational skin disease in Singapore. All patients diagnosed with occupational dermatoses in the National Skin Centre, Singapore, over the 10-year period 1989-1998 were studied retrospectively. Irritant contact dermatitis was found to be more common than allergic contact dermatitis. The major sources of occupational dermatitis in Singapore were the metal/engineering, building/construction, electrical/electronics and transport industries. The main irritants were detergents/wet work, solvent and oil/grease. The main allergens were chromate, rubber chemicals and nickel. We concluded that the main sources of occupational skin disease and main allergens in Singapore had remained the same compared to a similar study of occupational skin diseases in 1984-85. Weak irritants are still the predominant causes of occupational irritant contact dermatitis, though the main irritants have changed compared to the previous study, where cutting fluids, cement and solvent were the most common irritants.     

Pathological findings in cumulative irritation induced by SLS and croton oil in hairless mice

It is known that the pathological features of acute irritant contact dermatitis are specific according to the irritant. However, in chronic irritant contact dermatitis, it is not clear whether specific patterns exist. To investigate whether the specific pathology of acute irritant contact dermatitis is sustained in chronic irritant contact dermatitis, sodium lauryl sulfate (SLS) and croton oil were applied 3x a week for 2 weeks on the dorsal skin of hairless mice using Finn Chambers. The pathologic changes induced by irritants at various concentrations were evaluated using H&E and Luna's staining, as well as immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU), keratin 6 and loricrin. Our results showed that epidermal hyperplasia and inflammatory infiltration were relatively marked in the groups treated with higher concentrations of irritants. These features were more prominent in the 1% croton oil treated group than in the 0.25% SLS treated group. However, lower concentrations of irritants resulted in very similar histological changes, characterized by epidermal hyperplasia with minimal inflammatory infiltration, irrespective of the chemical. Our results suggest that the histological responses to irritants vary with concentration in cumulative irritation, as in acute irritation, but repetitive mild irritation may evoke common histological changes, characterized by epidermal hyperplasia with minimal inflammatory infiltration, irrespective of the chemical used.     

Epidermale Barrierestörung bei Dermatosen

The permeability barrier plays an important role in numerous skin diseases. Particularly well known is the importance of this barrier in eczema. In irritative–toxic contact dermatitis, the first step in the pathogenesis is the disturbance of the permeability barrier by irritative–toxic noxious substances. Only after damage to the barrier is achieved can irritants and allergens penetrate into the living epidermis. In atopic eczema due to an impaired barrier, allergens penetrate from the environment into the skin and cause or worsen the eczema. In psoriasis—the other common chronic inflammatory dermatosis—the role of the permeability barrier is only partly understood. In exanthema, infectious agents or drugs cause systemic inflammation, whereby the inflammation of the skin is followed by a barrier disorder. In principle, disturbed permeability of the skin barrier is present in all inflammatory diseases.     

Irritants in combination with a synergistic or additive effect on the skin response: an overview of tandem irritation studies

Sodium lauryl sulfate (SLS) has often been chosen as a model for irritant contact dermatitis (ICD) to study the effect of irritants in combination (1-14). Recently 'tandem', or sequential, exposures with SLS have been performed to study the mechanism of skin barrier impairment in ICD (1-6, 15). The assessment of reactions have been documented with visual scoring, transepidermal water loss (TEWL), skin colour reflectance measurements, skin blood flow; among which TEWL has been noted as the most sensitive value (16). The matched control groups were treated with either a single exposure to a single irritant or in tandem with the same irritant repeatedly. Synergistic and additive effects have been reported for various tandem pairs of irritants, however, the mechanism for both remains unclear. The results of tandem irritation studies were evaluated to define and investigate the responses produced and deduce a possible mechanism of action. Clinical ramifications, albeit complex, are discussed.     

The role of CD44 in cutaneous inflammation

Abstract:  CD44 is a transmembrane glycoprotein expressed in various tissues including the skin. Previous studies indicated that CD44 is required for epidermal permeability barrier homeostasis and keratinocyte differentiation. Yet, while some studies have demonstrated that CD44 is critical for the development of inflammation, others have shown that CD44 is not essential for the development of cutaneous inflammation. In this study, we evaluated the changes in epidermal CD44 expression in a variety of skin inflammatory models and determined whether CD44 is required for the development of cutaneous inflammation. Inflammatory responses were compared in CD44 KO versus wild-type mice in acute models of irritant and allergic contact dermatitis, as well as in a subacute allergic contact dermatitis induced by repeated hapten treatment. Inflammatory responses were assessed by measuring ear thickness and epidermal hyperplasia in haematoxylin & eosin-stained sections. Our results demonstrate that: (i) epidermal CD44 expression increases in both acute and subacute cutaneous inflammatory models; and (ii) acute disruption of the epidermal permeability barrier function increases epidermal CD44 expression. Whereas inflammatory responses did not differ between CD44 KO and wild-type mice in acute models of irritant and allergic contact dermatitis, both inflammatory responses and epidermal hyperplasia increased in CD44 KO mice following repeated hapten challenges. These results show first, that permeability barrier disruption and inflammation stimulate epidermal CD44 expression, and second, that CD44 modulates epidermal proliferation and inflammatory responses in a subacute murine allergic contact dermatitis model.     

Common pathogenetic pathways in allergic and irritant contact dermatitis.

Despite their different pathogeneses, allergic and irritant contact dermatitis show a remarkable similarity with respect to clinical appearance, histology, and immunohistology. To further analyze this apparent contradiction, our study was designed to meticulously compare cellular infiltrates in irritant and allergic patch-test reactions by immunostaining with a broad panel of monoclonal antibodies. For this purpose, skin biopsies from allergic and irritant patch-test reactions of similar inflammatory degree were obtained from the same probands. We found that after 72 h both types of reaction were characterized by an identical dermal infiltrate consisting mainly of memory T cells, many of which were activated, and macrophages. Dermal and epidermal Langerhans cell density and HLA--DR expression of keratinocytes were also virtually identical. Our results show that antigen recognition by specific memory T cells as well as irritants can finally induce the same pattern of inflammation, including activation of T cells obviously independent of exogenous antigen.     

Chinese herbal medicine (Tuhuai extract) exhibits topical anti-proliferative and anti-inflammatory activity in murine disease models

Abstract:  While psoriasis is one of the most common skin disorders in humans, effective, safe and inexpensive treatments are still largely unavailable. Chinese herbal medicine (CHM) has been used for centuries for treating psoriasis and several reports claim that systemic administration of one such CHM, Tuhuai, mainly composed of flos sophorae, smilax glabra roxb and licorice, is effective in psoriasis. However, the mechanisms by which this CHM improves psoriasis are not yet clear. Two universal features of psoriasis are epidermal hyperplasia and inflammation. Moreover, drugs that specifically inhibit epidermal hyperplasia and/or inflammation are widely used to treat psoriasis. Here, we investigated whether topical applications of Tuhuai extract exhibit anti-proliferative and anti-inflammatory activities in two murine models of inflammatory dermatoses. To assess Tuhuai's potential anti-proliferative effect, we disrupted epidermal barrier function twice-daily for 4 days in normal hairless mice followed by topical applications of either 1% Tuhuai extract or Vehicle to both flanks immediately after each barrier perturbation. Changes in epidermal proliferation and apoptosis were evaluated by immunohistochemistry and TUNEL staining. To assess the anti-inflammatory effects of Tuhuai, both irritant (phorbol ester) and acute allergic contact dermatitis (oxazolone) models were used. Whereas topical Tuhuai extract did not alter epidermal proliferation or induce irritation in normal skin, it both reduced epidermal hyperplasia in the epidermal hyperproliferative model, and reduced inflammation in both irritant and allergic contact dermatitis models. As topical Tuhuai extract exhibits anti-proliferative and anti-inflammatory properties in a variety of human models of inflammatory dermatoses, Tuhuai could provide an effective, relatively safe and inexpensive therapeutic alternative for the treatment of inflammatory dermatoses, including psoriasis.     

Combined effects of irritants and allergens. Synergistic effects of nickel and sodium lauryl sulfate in nickel- sensitized individuals

Knowledge of the combined effects of irritants and allergens is of interest with respect to accurate risk assessment. The threshold for elicitation of allergic contact dermatitis in previously sensitized individuals may theoretically be markedly influenced by the simultaneous presence of irritants and allergens. Combined exposures have, however, only been studied infrequently. In the present study, the combined effect of an irritant and an allergen was evaluated in a dose-response designed experimental study. 20 nickel-sensitized subjects were exposed to patch testing with varying concentrations of NiCl2 (nickel chloride) and sodium lauryl sulfate (SLS) alone and in combination. Evaluation of skin reactions was performed by colorimetry, measurement of transepidermal water loss and clinical evaluation, and the data were analyzed by logistic dose-response models. A synergistic effect was found of combined exposure to NiCl2 and SLS, as compared to each of the substances applied separately, as evaluated by colorimetry and clinical scoring. This means that the effect produced by the combined exposure was substantially greater than the effect produced by either of the substances alone. A synergistic effect of combined exposure on skin barrier impairment was not found, since the barrier function is significantly influenced by SLS-exposure only and not by NiCl2. Concentration limits are used by industry and government agencies to protect consumers. The present results clearly illustrate that elicitation thresholds and concentration limits may be influenced considerably by combined exposure to allergens and irritants.     

Contact allergens and sodium lauryl sulphate upregulate vascular endothelial growth factor in normal keratinocytes

In allergic and irritant contact dermatitis, keratinocytes are major target cells that can be activated to take part in local reactions by secreting soluble mediators. Among the growth factors produced by keratinocytes, vascular endothelial growth factor (VEGF) is a powerful inducer of permeability of endothelial cells, and is involved in inflammation. We determined whether different contact allergens, dinitrosulphobenzene (DNSB), para-phenylenediamine (pPD) and the metals nickel and chromium, as distinct from cobalt, which has been shown to mimic the effects of hypoxia, can modify the basal level of VEGF in normal human keratinocytes when tested at various, non-toxic concentrations. The effects of an irritant, sodium lauryl sulphate (SLS), and of hydrocortisone were also tested. Our results showed an intense dose-dependent upregulation of VEGF release by keratinocytes after treatments by metals, pPD and SLS. DNSB induced only a moderate increase of VEGF. Hydrocortisone reduced the basal level as well as the nickel-induced upregulation of VEGF. These findings suggest that contact allergens and irritants probably upregulate VEGF in keratinocytes by different mechanisms and may contribute directly to the microvascular hyperpermeability which characterizes both contact and irritant dermatitis.     

Evolving concepts of pathogenesis in atopic dermatitis and other eczemas

The eczemas represent a common and diverse group of inflammatory skin diseases whose definitions and pathogenic mechanisms have often been confused and controversial. Since the millennium, fresh approaches are providing better insight. Research has focused much more upon the epidermis and the very relevant signaling pathways that contribute to spongiosis, proliferation, generation of proinflammatory factors, and differentiation to form an effective stratum corneum barrier. A major step in understanding has come from the solidly confirmed association between filaggrin null mutations of ichthyosis vulgaris and atopic dermatitis. Similar associations relating to protease and lipid defects have highlighted the role of barrier disruption that allows greater access of environmental toxins, microbes, and allergens. Animal models are beginning to predict mechanisms in which such direct perturbation of keratinocytes may initiate inflammation and condition immune responses in irritant contact dermatitis and atopic dermatitis. These conceptual shifts are nurturing more balanced approaches to understanding eczema and hold the hope for better prevention efforts and more specific molecular targeting for therapy.