Skin barrier homeostasis

C. Role of Calcium Ions in the Regulation of Skin Barrier Homeostasis... 

The importance of calcium in the regulation of skin barrier homeostasis is apparent as calcium is involved in the regeneration process of skin barrier components.4 Hence, the balance of calcium level in skin is closely related to hydration of the skin. Apart from the skin, this ion plays a crucial role in various processes in the body, including the growth, death, differentiation, and function of immune cells. The role of calcium in skin is found to be more complex than previously assumed. The elucidation of calcium regulation mechanism in skin could be useful to understand and solve skin problems. 

Topical application of an ionic polymer forms a diffusion electric double layer on the surface of the skin. We evaluated the effects of topical application of ionic polymers on the recovery rate of the skin barrier after injury. Application of a nonionic polymer did not affect the barrier recovery. Application of sodium salts of anionic polymers accelerated the barrier recovery, while that of cationic polymers delayed it. Topical application of a sodium-exchange resin accelerated the barrier recovery, but application of a calcium-exchange resin had no effect, even when the resins had the same structure. Application of a chloride-exchange resin delayed barrier recovery. Thus, topical application of ionic polymers markedly influenced skin barrier homeostasis (Figure 15.2). 

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. 

Water homeostasis is a strict requirement for normal physiological function. The most important task of the human skin is thus to create a watertight enclosure of the body to prevent water loss. It is the intercellular lipid matrix of the outermost keratinized horny layer of the skin (possibly together with recently reported claudin-based tight-junctions Furuse et al., 2002) that represents the skin barrier proper as once this lipid matrix (composed foremostly of saturated long chain ceramides ( 50% wt/wt) and cholesterol (—30% wt/wt) (Wertz and Norlen, 2002)) has been removed, substances diffuse freely into or out of the body system (Blank, 1952 Breathnach et al., 1973 Elias and Friend, 1975). At the same time the intercellular lipid matrix ensures that the stratum corneum remains hydrated and thus the skin surface appears healthy and smooth. 

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. 

Recent studies suggested that intrinsic factors also affect cutaneous barrier homeostasis. Psychological stress delays barrier recovery after artificial barrier disruption.11 Also, the SC barrier becomes fragile and the recovery rate is delayed with aging.12 Thus, a dry skin model induced by barrier disruption might be a good model for clinical research. 

Denda et al. previously demonstrated40 that tran.s-4-aminomethyl cyclohexane carboxylic acid (/-AMCIIA), an anti-fibrinolytic agent that activates plasminogen, improved the barrier homeostasis and whole skin condition. After barrier disruption, proteolytic activity in the epidermis increased within 1 to 2 h. This increase was inhibited by t-AMCHA. Topical application of r-AMCHA or... 

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. 

Several new strategies are available to accelerate skin permeability barrier recovery after injury. Here, I will describe our recent work on improving barrier homeostasis with new reagents and new materials, and discuss the implications for clinical dermatology. 

Denda, M., Nakanishi, K. and Kumazawa, N., Topical application of ionic polymers affects skin permeability barrier homeostasis. Skin Pharmacol. Physiol. 18 36—41, 2005. 

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. 

Halkier-Sorensen L, Thestrup-Pedersen K (1991) The relationship between skin surface temperature, transepidermal water loss and electrical capacitance among workers in the fish processing industry comparison with other occupations. A field study. Contact Dermatitis 24 345-355 Halkier-Sorensen L, Menon GK, Elias PM, Thestrup-Pedersen K, Feingold KR (1995) Cutaneous barrier function after cold exposure in hairless mice a model to demonstrate how cold interferes with barrier homeostasis among workers in the fish-processing industry. Br J Dermatol 132 391-401... 

The exact mechanism of action of moisturizers and emollients is still unknown. Theoretically, the improvement in the barrier function could be due to absorption of the moisturizer into the delipidized stratum corneum, acting as an effective barrier, as suggested in a study on the effect of petrolatum (Ghadially et al. 1992). Due to a better knowledge of the structural organization of the horny layer with corneocytes embedded in between lipid bilayers (ceramides, cholesterol and free fatty acids in approximately equal quantities), new emollients could be developed to supply the missing elements in the bilayer structure after acute or chronic irritant contact. However, applications of ceramides, linoleic acid and a variety of other fatty acids alone have been reported to actually delay barrier recovery in acetone-treated murine skin, despite the fact that these lipids are required for barrier homeostasis. The only treatments that allowed normal barrier recovery were applications of complete mixtures of ceramide, fatty acid and cholesterol, or pure cholesterol (Man et al. 

The stratum corneum consists of separated, nonviable, cornified, almost nonpermeable corneocytes embedded into a continuous lipid bilayer made of various classes of lipids, for example, ceramides, cholesterol, cholesterol esters, free fatty acids, and triglycerides [6], Structurally, this epidermis layer is best described by the so-called brick-and-mortar model [7], The stratum corneum is crucial for the barrier function of the skin, controlling percutaneous absorption of dermally applied substances and regulating fluid homeostasis. The thickness of the stratum corneum is usually 10-25 /an, with exceptions at the soles of the feet and the palms, and swells several-fold when hydrated. All components of the stratum corneum originate from the basal layer of the epidermis, the stratum germinativum. 

Although the stratum corneum acts as a simple physical barrier to outside influences, skin tissue as a whole is very active. It is crucial in maintaining the body s homeostasis, its essential steady-state environment. Skin maintains temperature and balance of electrolytes, the dissolved salts in internal body fluids. It is metabolically active and participates in hormonal and immune regulatory processes. More than serving as a passive barrier, it is proactive in response to xenobiotic insults and can be damaged in the defensive process by developing rashes and other symptoms. 

The stratum comeum is usefully thought of as a brick wall , with the fully differentiated comeocytes comprising the bricks , embedded in the mortar created by the intercellular lipids. A layer of lipid covalently bound to the comified envelope of the comeocyte contributes to this exquisite organization. The intercellular lipids of the stratum comeum include no phosphohpids, comprising an approximately equimolar mixture of ceramides, cholesterol and free fatty acids. These non-polar and somewhat rigid components of the stratum comeum s cement play a critical role in barrier function. On average, there are about 20 cell layers in the stratum comeum, each of which is about 0.5 fim in thickness. Yet, the architecture of the membrane is such that this very thin structure limits, under normal conditions, the passive loss of water across the entire skin surface to only about 250 mL per day, a volume easily replaced in order to maintain homeostasis. 

The skin is the largest organ in the human body and has many physiological functions. The skin serves to regulate overall body homeostasis, protect the body from external pathogens and chemicals, as well as control water loss from the body. The skin has three main layers. The epidermis, which is the outermost layer, is the thinnest layer of the skin and provides the most significant barrier function [7]. Beneath the epidermis, the dermis provides mechanical support to the skin and the third layer, immediately under the dermis, is a layer of subcutaneous fat called the hypodermis. 

Skin repair after a peel to the reticular dermis is slower, as all the basal layer keratinocytes have been destroyed and the skin can only rely on the differentiated keratinocytes of the pilosebaceous units and the intradermal excretory ducts of the sweat glands. To repair the dermis, the sebocytes in the pilosebaceous units must dedifferentiate, and horizontal growth is required to close the skin quickly. Next comes a phase of vertical growth whose purpose is to regenerate a physiologically sound epidermis that will maintain homeostasis and restore the vital barrier function after the keratinocytes have differentiated into corneocytes. 

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