Skin-barrier function

A. P. M. Lavrijsen, J. A. Bouwstra, G. S. Gooris, A. Weerheim, H. E. Bodde, and M. Ponec. Reduced skin barrier function parallels abnormal stratum comeum lipid organization in patients with lamellar ichthyosis. J. Invest. Dermatol. 105 619-624 (1995). 

Notman, R., Anwar, J., Briels, W.J., Noro, M.G., den Otter, W.K. Simulations of skin barrier function free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers. Biophys. J. 2008, 95, 4763-71. 

Compounds that penetrate the stratum corneum via the transepidermal route may follow a transcellular (or intracellular) or intercellular pathway (see Figure 11.1). Because of the highly impermeable character of the cornified envelope (see previous section), the tortuous intercellular pathway has been suggested to be the route of preference for most drug molecules [32], This is confirmed by several microscopic transport studies, in which compounds have been visualized in the intercellular space of the stratum corneum [33-35]. Moreover, it has been demonstrated that drug permeation across stratum corneum increases many folds after lipid extraction [36], Hence, knowledge of the structure and physical properties of the intercellular lipids is crucial to broaden our insight into the skin barrier function. 

In recessive X-linked ichthyosis, the amount of cholesterol sulfate in the stratum corneum is increased due to a deficiency in cholesterol sulfatase deficiency [69,70], Lipid analysis of scales reveals a nearly 10-fold increase in the cholesterol sulfate to free cholesterol ratio as compared to healthy stratum corneum [71]. Previous x-ray diffraction studies on isolated ceramide mixtures revealed that increased cholesterol sulfate levels induce the formation of a fluid phase, which is likely to reduce the skin barrier function [72]. 

The experimental protocol involved three consecutive stages of treatment to the same HEM a first passive permeation stage, which lasted for 3 h, followed by a 2 h electrical treatment period during which electroporation or iontophoresis or both protocols were applied to the skin and finally a second passive stage (2 h) evaluated possible reversibility of skin barrier function following electrical treatment. 

Mikszta, J.A., et al. 2002. Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat Med 8 415. 

Song, J.Y., et al. 2004. Damage and recovery of skin barrier function after glycolic acid chemical peeling and crystal microdermabrasion. Dermatol Surg 30 390. 

A permeation enhancer can be defined as a compound that alters the skin barrier function so that a desired drug can permeate at a faster rate. Dozens of enhancers are patented each year, and several books have been written summarizing the work and proposing mechanisms of enhancement.70-72 The permeation enhancers may be classified simply as polar and nonpolar ones. They can be used individually or in combination, such as binary mixtures. For several drugs, the flux across skin was observed to be linear with that of the most widely used enhancer, ethanol.73-75 Another polar enhancer, isopropanol, facilitated ion association of charged molecules and enhanced the transport of both neutral and ionic species across the stratum corneum.76 77 While polar enhancers traverse the skin, nonpolar enhancers are largely retained in the stratum corneum both aspects make the combination a superior enhancer to the individual enhancers.78... 

McGrath, J. A. and Uitto, J. (2008) The filaggrin story novel insights into skin-barrier function and disease. Trends Mol Med 14, 20-27. 

This chapter will deal with the stratum corneum barrier with a special focus on structure-function relationships. For this reason our approach has been to describe some details of the epidermal physiology that have a bearing on upholding the barrier function. We see it as important that skin barrier function is regarded as part of the dynamic processes of cellular transformation during the differentiation of epidermal keratinocytes, hence dependent on the status of the skin. 

Norlen, L. et al., Differences in human stratum corneum lipid content related to physical parameters of skin barrier function in vivo, J. Invest. Dermatol., 112, 72, 1999. 

Engblom, J., On the Phase Behaviour of Lipids with Respect to Skin Barrier Function, Thesis. Lund University, Sweden, 1996. 

Rawlings, A.V. and Harding, C.R., Moisturization and skin barrier function, Dermatol. Then 17 (Suppl. 1), 43-8, 2004. 

Tanojo, H. and Maibach, H.I., Role of calcium ions in relation to skin barrier function, in Percutaneous Absorption Drugs-Cosmetics—Mechanisms-Methodology, 3rd ed., Bronaugh, R.L. and Maibach, H.I. Eds., New York, Marcel Dekker 1999, pp. 939-950. 

Proksch, E. Nissen, H-P. Bremgartner, M. Urquhart, C., Bathing in a magnesium-rich Dead Sea salt solution improves skin barrier function, enhances skin hydration, and reduces inflammation in atopic dry skin. Int. J. Dermatol. 44, 151-157, 2005. 

Ny, A. and Egelrud, T., Epidermal hyperproliferation and decreased skin barrier function in mice overexpressing stratum corneum chymotryptic enzyme, Acta Derm. Venereol., 84, 18, 2004. 

AD patients showed mild inflammation with induction of the parakeratosis, decreased moisture holding ability, and inferior barrier function, while HD patients showed only reduced moisture holding ability with almost normal skin barrier function but without inflammation. Then, it was concluded that the dry skin of AD patients resulted from the lack of moisture holding factor (free amino acids, NMF) and inferior barrier function of SC, while that in HD patients was mainly attributed to the decrease of the moisture holding factors. 

Histamine receptors are related to skin barrier function.44 Three different types of histamine receptors, HI, H2, and H3 have been reported. First, topical application of histamine HI and H2 receptor antagonists accelerated the barrier repair. Histamine itself, H2 receptor agonist, and histamine releaser delayed the barrier repair. Histamine H3 receptor antagonist and agonist did not affect the barrier recovery rate. Topical application of the HI and H2 receptor antagonists prevented the epidermal hyperplasia induced by barrier disruption under low humidity. The mechanism of the relationship between the histamine receptors and the barrier repair process has not been elucidated yet. 

Leveque, J.L., de Rigal, J., Saint-Leger, D., and Billy, D. (1993) How does sodium lauryl sulfate alter the skin barrier function in man A multiparametric approach. Skin Pharmacol. 6 111-115. 

Several neural receptors have been isolated recently within the epidermis of humans and mice. Many of these receptors, such as vanilloid receptor 1, are associated with ion dynamics in the peripheral nervous system.38 Since skin barrier function is also predicated on ion gradient stability,15,39 these receptors might be inducing transmission of itch related to barrier impairment. 

Considerations about skin pH can be divided into two parts the outside and inside skin pH. The former applies to the skin surface and the latter to the pH-profile across the epidermis. In the following chapter, the inside and outside skin pH is addressed, as well as its importance and influence on skin barrier function. A short review of methods used to measure the pH is presented as well. 

The difference in skin pH between sexes is also questionable. Few studies show a difference, with men having lower pH than women,24-27 while others do not.18,28 It is suggested, that possible pH difference between men and women can be due to sex-hormones, which influence skin barrier function.13... 

The considerations mentioned earlier also bring up the subsequent questions that wait to be answered, for example, about the influence of moisturizers on pH-gradient inside the epidermis and the activity of enzymes, effect on skin barrier function and skin barrier recovery, or the difference in... 

Similarly as in case of stay-on products, there are several questions waiting to be answered about the impact of pH of rinse-off cleansing products on the skin, its pH, and the skin barrier function. One of the issues investigated was the influence on skin microflora, showing that when skin pH increased after repeated use of an alkaline soap, the count of propionibacteria rose significantly 64 Moreover, the irritancy properties of cleansing products have often been associated with their pH, but several studies show that there is no direct correlation between those two features.62,68-70 The reported difference in irritancy potential between cleansers with various pH may depend on the combination of surfactants and their inherent irritating capacity, rather than the pH of the products.61... 

Rippke, F. etal., Stratum corneum pH in atopic dermatitis impact on skin barrier function and colonization with Staphylococcus aureus, Am. J. Clin. Dermatol., 5, 217, 2004. 

Different types of evidence can be ranked in term of importance when decisions about clinical interventions are made (Figure 19.1).13,14 For example, the confidence from randomized controlled trials gives stronger evidence for treatment effects than open studies. Moreover, apparently conflicting results between studies may be compatible when a statistical meta-analysis of the data has been performed. This chapter will give a brief summary of evidence on the treatment effects of common dry skin disorders with urea-formulations. Furthermore, data on the influence of urea on the skin barrier function will be reviewed. 

Influence of Urea-Treatment on Skin Barrier Function in Normal Skin... 

FIGURE 19.2 Moisturizers can be divided into four groups depending on their effect on dryness and skin barrier function. 

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