In vitro skin irritation: facts and future. State of the art review of mechanisms and models

Magnesium salts, the prevalent minerals in Dead Sea water, are known to exhibit favorable effects in inflammatory diseases. We examined the efficacy of bathing atopic subjects in a salt rich in magnesium chloride from deep layers of the Dead Sea (Mavena(R) Dermaline Mg(46) Dead Sea salt, Mavena AG, Belp, Switzerland). Volunteers with atopic dry skin submerged one forearm for 15 min in a bath solution containing 5% Dead Sea salt. The second arm was submerged in tap water as control. Before the study and at weeks 1-6, transepidermal water loss (TEWL), skin hydration, skin roughness, and skin redness were determined. We found one subgroup with a normal and one subgroup with an elevated TEWL before the study. Bathing in the Dead Sea salt solution significantly improved skin barrier function compared with the tap water-treated control forearm in the subgroup with elevated basal TEWL. Skin hydration was enhanced on the forearm treated with the Dead Sea salt in each group, which means the treatment moisturized the skin. Skin roughness and redness of the skin as a marker for inflammation were significantly reduced after bathing in the salt solution. This demonstrates that bathing in the salt solution was well tolerated, improved skin barrier function, enhanced stratum corneum hydration, and reduced skin roughness and inflammation. We suggest that the favorable effects of bathing in the Dead Sea salt solution are most likely related to the high magnesium content. Magnesium salts are known to bind water, influence epidermal proliferation and differentiation, and enhance permeability barrier repair.

Bathing in a magnesium-rich Dead Sea salt solution improves skin barrier function, enhances skin hydration, and reduces inflammation in atopic dry skin.

Irritant contact dermatitis is a result of activated innate immune response to various external stimuli and consists of complex interplay which involves skin barrier disruption, cellular changes, and release of proinflammatory mediators. In this review, we will focus on key cytokines and chemokines involved in the pathogenesis of irritant contact dermatitis and also contrast the differences between allergic contact dermatitis and irritant contact dermatitis.

/pdf/cytokines-and-chemokines-in-irritant-contact-dermatitis-38tgsmntw3.pdf

Cytokines and chemokines in irritant contact dermatitis.

Use of RT-PCR and DNA Microarrays to Characterize RNA Recovered by Non-Invasive Tape Harvesting of Normal and Inflamed Skin

Background: The ribonuclease protection assay (RPA) represents a technology that allows detection of small amounts of intact RNA. Recent progress in understanding cytokine networks in the skin suggests that measurements of cytokine mRNA levels could provide a method to distinguish various reactions such as irritant contact dermatitis and allergic contact dermatitis that can occur in the skin. Objective: We attempted to differentiate and quantitate irritant and immunologic skin reactions by measuring mRNA levels. Methods: We have used the technique of tape stripping human skin to remove superficial cell layers and have extracted RNA from these skin samples. This RNA was used for RPA analysis. Results: By means of RPA analysis, we have demonstrated distinct cytokine profiles that appear to discriminate, for example, irritant from immunologic skin reactions. Conclusion: We have shown that multiple cytokine mRNA levels can be defined in these RNA samples obtained from the skin. This approach assesses not only the cytokine gene profiles, but at the same time may quantify the severity of common irritant versus allergic skin reactions. (J Am Acad Dermatol 1999;41:687-92.)

A noninvasive method for quantifying and distinguishing inflammatory skin reactions.

The epidermal response to 2 different irritants, nonanoic acid (NAA) and sodium lauryl sulfate (SLS), was investigated with 2 different methods. NAA 80% and SLS 4% were applied under occlusion for up to 24 h. Elemental changes were determined in cryosections by x-ray microanalysis. Compared to unexposed skin a significantly higher sodium/potassium ratio was found after 6 h in NAA-exposed skin and a lower ratio in SLS-exposed. At 24 h both substances had induced similar changes, compatible with a cell injury. The findings demonstrate a time-dependent NAA and SLS response. With reverse transcription polymerase chain reaction, the mRNA expression of interleukin-1 alpha (IL-1 alpha), -1 beta (IL-1 beta), -6 (IL-6), and -8 (IL-8), tumor necrosis factor alpha (TNF alpha) and granulocyte macrophage colony stimulating factor (GM-CSF) in shave biopsies from irritated and unexposed skin was studied at 0. 4. 8 and 24 h. NAA, but not SLS, induced an increase in mRNA expression for IL-6 mRNA-expression for GM-CSF was increased after SLS exposure, but not after NAA. These findings indicate a time and substance dependent difference in the up-regulation of mRNA for different cytokines in epidermis during the first 24 h of the irritant reaction. This might be the effect of differences in the irritants action on the cell membranes, which is also reflected by the differences found in the elemental content at 6 h.

Different pathways in irritant contact eczema? Early differences in the epidermal elemental content and expression of cytokines after application of 2 different irritants.

Keratinocyte proliferation in normal human skin was induced by application of irritants: sodium lauryl sulfate (SLS) or non-anoic acid (NAA). Each irritant was applied at three different concentrations to normal human skin in vivo under occlusion for 24 h. The irritative response was visually assessed for erythema, and the number of cycling cells was calculated from the number of Ki67 positive cells in cryosections from skin biopsies taken at 0, 24, 48, 72 and 96 h. In addition, to determine the elemental content of the epidermal cells during the response, two epidermal strata were examined by X-ray microanalysis (XRMA). Both the application of SLS and that of NAA resulted in erythema, and the number of Ki67 positive cells was increased at 48 h. XRMA revealed an initial increase in the sodium/potassium (Na/K) ratio, indicating cell membrane injury. Due to an increasing potassium (K) concentration the Na/K ratio decreased after 24 h, which is compatible with proliferation, in accordance with the Ki67 data. This was more evident in SLS-stimulated skin, where also the concentrations of magnesium (Mg) and phosphorus (P) increased, an observation commonly made in proliferating cells. It appears that application of SLS results in a period of cell damage lasting about 24-48 h, followed by a period of proliferation. The effects of NAA appear more complicated, and proliferation may take place in parallel with cell damage.

Irritant-induced keratinocyte proliferation evaluated with two different methods: immunohistochemistry and X-ray microanalysis.

The effect of local anaesthesia on the elemental content of cells in human epidermis was studied by electron probe X-ray microanalysis. Local anaesthesia with lidocaine was given by intracutaneous injection within 1 min prior to taking a skin biopsy. Biopsies taken without local anaesthesia were used as controls. Lidocaine with or without adrenaline caused a significant increase in the concentrations of Na and Cl, and a decrease in the concentration of K in the cells of the stratum basale and the stratum spinosum, compared with the control samples. The presence of adrenalin in the anaesthetic did not change the effect of lidocaine. The effects of local anaesthesia have to be considered in planning and interpretation of clinical applications of X-ray microanalysis.

Methods for X-ray microanalysis of epidermis: the effect of local anaesthesia.

Irritant substances have been shown to induce elemental changes in human and animal epidermal cells in situ. However, skin biopsies are a complicated experimental system and artefacts can be introduced by the anaesthesia necessary to take the biopsy. We therefore attempted to set up an experimental system for X-ray microanalysis (XRMA) consisting of cultured human keratinocytes. A number of methodological aspects were studied: different cell types, washing methods and different culture periods for the keratinocytes. It was also investigated whether the keratinocytes responded to exposure to sodium lauryl sulphate (SLS) with changes in their elemental composition. The concentrations of biologically important elements such as Na, Mg, P and K were different in HaCaT cells (a spontaneously immortalized non-tumorigenic cell line derived from adult human keratinocytes) compared to natural human epidermal keratinocytes. The washing procedure and time of culture influenced the intracellular elemental content, and rinsing with distilled water was preferred for further experiments. Changes in the elemental content in the HaCaT cells compatible with a pattern of cell injury followed by repair by cell proliferation were seen after treatment with 3.33 µm and 33 µm SLS. We conclude that XRMA is a useful tool for the study of functional changes in cultured keratinocytes, even though the preparation methods have to be strictly controlled. The method can conceivably be used for predicting effects of different chemicals on human skin.

X-ray microanalysis of cultured keratinocytes: methodological aspects and effects of the irritant sodium lauryl sulphate on elemental composition.

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Different pathways in irritant contact eczema? Early differences in the epidermal elemental content and expression of cytokines after application of 2 different irritants.

Irritant-induced keratinocyte proliferation evaluated with two different methods: immunohistochemistry and X-ray microanalysis.

Methods for X-ray microanalysis of epidermis: the effect of local anaesthesia.

X-ray microanalysis of cultured keratinocytes: methodological aspects and effects of the irritant sodium lauryl sulphate on elemental composition.