**4.1 Endocrine factors**

204 Atopic Dermatitis – Disease Etiology and Clinical Management

accelerated barrier recovery, while allose, galactose, glucose and gulose had no effect. Among the 4 dextro-ketohexoses, psicose, fructose, sorbose and tagatose all accelerated barrier recovery. Because the effects of hexoses on the barrier recovery rate appeared within one hour, the mechanism is unlikely to be genomic. Instead, these hexoses may influence phase transition of the lipid bilayers of lamellar bodies and cell membrane, a crucial step in

Lipids play a crucial role in the water-impermeable barrier function of the skin. Damaged barrier function can be restored by topical application of a water-impermeable substance such as petrolatum (Man 1995). In this case, the petrolatum stays in the stratum corneum and forms a water-impermeable membrane. However, Man et al. demonstrated that a topically applied mixture of stratum corneum lipids, i.e., ceramide, cholesterol and free fatty acids, was incorporated in the nucleated layer of epidermis and accelerated repair of the barrier function after damage (Man 1996). They were the first to report a method to accelerate the barrier recovery by regulating endogenous factors in the epidermis. Interestingly, when they applied ceramide, cholesterol, or free fatty acid alone, or a mixture of two of these, the barrier recovery was delayed. Only when they applied a mixture of all three lipids at a specific relative ratio was the barrier recovery accelerated (Man 1996). These results suggest that a balance of the three lipids is crucial for skin barrier homeostasis.

Physical factors Accelerate barrier

(Denda 2010a,b) 10~15oC (1 min)

Sound (Denda&Nakatani 2010) 10~30 kHz

Metal (Denda& Kumazawa 2010) Pt, Au, Ag, In, Zr, Sm

Hexose (Denda 2011) most hexoses

Chemical factors

Physiological lipids balanced mixture

permeability barrier recovery.

Temperature (Denda 2007) 36~40oC (1 hour) >42oC

Ionic polymers (Denda 2005) sodium salt anionic cationic Barium sulphate (Fuziwara 2004) negative positive

Ions (Lee 1991) (Denda 1999) magnesium calcium, potassium

In the case of aging, different treatment might be necessary because of the different metabolism of aged skin. Ghadially et al. demonstrated that skin barrier function in elderly subjects was destroyed more easily than that in young individuals (Ghadially 1995). Moreover, the barrier recovery rate after barrier disruption was significantly slower for the elderly subjects than for younger ones. The same tendency was observed in both humans and hairless mice. They also suggested that synthesis of cholesterol is reduced more than that of other lipids, i.e., ceramide and fatty acids, in aged mice. The delay of barrier recovery

(Man 1996) balanced mixture unbalanced

Table 1. Summary of the effects of physical, chemical and biological factors on skin

Visible light (Denda 2008) Red (550~670 nm) Blue (430~510 nm) Electrical potential (Denda&Kumazawa 2002) Negative Positive

recovery

Delay barrier recovery

mixture

epidermal permeability barrier homeostasis.

**3.3 Physiological lipids** 

Sex hormones are strongly associated with epidermal permeability barrier homeostasis (Hanley 1996). Moreover, when the balance of these hormones alters at menopause or during the menstrual cycle, skin sensitivity or barrier function is changed. These results suggest that the relative composition of hormones influences barrier function and skin sensitivity. We recently studied the effects of topical application of sex hormones on the permeability barrier recovery rate of hairless mice after tape stripping (Tsutusmi and Denda 2007). Application of androgens, testosterone and androsterone, delayed barrier recovery. The delay was blocked by application of beta-estradiol. Application of progesterone also delayed barrier recovery. However, the delay was enhanced by the application of beta-estradiol. These results suggest that the alteration of the sex hormone balance at menopause or during the estradiol cycle might be the cause of skin problems at the corresponding period of time.
