Epidermal barrier homeostasis

The G-protein coupled receptors modulate intracellular cAMP level, which plays a crucial role in epidermal barrier homeostasis.5 Increase of intracellular cAMP in epidermal keratinocytes by topical application of forskolin delays barrier recovery, while cAMP antagonists accelerate the barrier recovery. Activation of dopamine 2-like receptors (manuscript in preparation), melatonin receptors, or serotonin receptor (type 5-HT1) decreases intracellular cAMP and consequently accelerates the barrier recovery (Figure 15.1), while activation of adrenergic 32 receptors increases intracellular cAMP and delays the barrier repair.6 Barrier disruption induces an increase of the intracellular cAMP level. Thus, topical application of agonists of receptors that reduce intracellular cAMP accelerates the barrier repair. Our results are summarized in Table. 15.1. 

Chapter 15 New Methodology to Improve Epidermal Barrier Homeostasis 155 Mitsuhiro Denda... 

Hachem, J.-P., Crumrine, D., Fluhr, J., Brown, B.E., Feingold, K.R., and Elias, P.M., pH directly regulates epidermal permeability barrier homeostasis, and stratum corneum integrity/cohesion, J. Invest. Dermatol., 121, 345-353, 2003. 

Dry, scaly skin is characterized by a decrease in the water retention capacity of the stratum corneum (SC),1 with water content diminished to less than 10%. Barrier function of the SC is usually declined, and transepidermal water loss (TEWL) is increased because of an abnormality on barrier homeostasis.2 People feel tightness of their skin, and the skin surface becomes rough, scaly, and sensitive. Hyperkeratosis, abnormal scaling, and epidermal hyperplasia are usually observed in the dry skin.2 Keratinization also shows abnormal features.2 These phenomena are commonly observed in atopic dermatitis and psoriasis.3 Dermatitis induced by environmental factors such as exposure to chemicals, low humidity, and UV radiation also shows these features. Thus, many researchers have been investigating the cause and treatment of dry skin, and there is currently great interest in adequate model systems for dry skin studies. In this chapter, I will describe several model systems of dry skin for clinical research of dermatitis associated with skin surface dryness and also mention recent studies to improve the dry skin. 

Not only ionotropic receptors but also metabotropic receptors are associated with cutaneous barrier homeostasis. /32-adrenergic receptor antagonist prevented epidermal hyperplasia induced by barrier disruption.48 In the case of metabotropic receptors, the level of intracellular cAMP in the epidermal keratinocytes is associated with cutaneous barrier homeostasis and epidermal hyperplasia.49... 

Elias, P.M., Holleran, W.M., Menon, G.K., Ghadially, R., Williams, M.L., and Feingold, K.R. (1993) Normal mechanisms and pathophysiology of epidermal permeability barrier homeostasis. Curr. Opin. Dermatol. 1 231-237. 

Denda, M., Fuziwara, S., and Inoue, K. (2003) Influx of calcium and chloride ions into epidermal keratinocytes regulates exocytosis of epidermal lamellar bodies and skin permeability barrier homeostasis. J. Invest. Dermatol. 121 362-367. 

Among the former group, receptors that act as calcium ion or chloride ion channels play a crucial role in epidermal permeability barrier homeostasis. Topical application of calcium channel agonists delays the barrier recovery, while antagonists accelerate barrier repair.1,2,3 Topical application of chloride ion channel agonists accelerates the barrier recovery.2,4 The results of our studies are summarized in Table 15.1. 

Structure of SC and its lipid content affect the permeability barrier function. Visualization studies revealed that the penetration route across the SC resides in the intercellular tortuous pathway between the corneocytes. This implies that SC lipids play a key role in the skin barrier function.27 Another major controlling element in barrier homeostasis seems to be the epidermal Calcium ion.28... 

EUas PM and Feingold KR. Coordinate regulation of epidermal differentiation and barrier homeostasis. Skin Pharmacol. Appl. Skin Physiol. 2001 14(Suppl. l) 28-34. 

Skin barrier functions can be mainly attributed to the outermost layer of mammalian epidermis, the stratum corneum (SC). This region consists of dead, cornified cells embedded in a matrix of extracellular lipids, containing mainly ceramides, cholesterol, cholesterol sulphate and free fatty acids. The SC lipids are organized in a specific lamellar, quasi-crystalline structure, which is critical for optimal skin barrier homeostasis. However, formation of the lamellar structure requires presence of the lipid subclasses in a defined ratio, and ceramides by weight comprise roughly 50% of total SC lipids. The structure and formation of the epidermal lipid barrier is explained in Figure 12.15. 

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