Barrier recovery

The process of barrier repair in connection with transepidermal water loss and calcium gradient is illustrated in Figure 6.2. Experiment in mice shows that the calcium gradient disappears after acute permeability barrier disruption, and returns after 6 h in parallel with barrier recovery, barrier... 

Man, M.Q., Mauro, T.M., Bench, G., Warren, R., Elias, P.M., and Feingold, K.R., Calcium and potassium inhibit barrier recovery after disruption, independent of the type of insult in hairless mice, Exp. Dermatol. 6, 36-40, 1997. 

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. 

Feingold and his coworkers demonstrated an important role of nuclear hormone receptor on epidermal differentiation and stratum corneum barrier formation. Activation ofPPARa Peroxisome proliferator-activated receptor a by farnesol also stimulated the differentiation of epidermal keratinocytes.42 Cornified envelope formation, involcrin, and transglutaminase protein, and mRNA levels were also increased by the activation of PPARo . Interestingly, the inflammatory response was also inhibited by the treatment.43 They also showed that topical application of PPARo activators accelerated the barrier recovery after tape stripping or acetone treatment and prevented the epidermal hyperplasia induced by repeated barrier disruption.42 Regulation of the nuclear hormone receptor would open a new possibility for improvement of the cutaneous barrier. 

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. 

Activation of calcium permeable receptors such as purinergic P2X receptor or NMDA receptor delayed the barrier recovery after barrier disruption and enhanced epidermal hyperplasia induced by barrier disruption.45-47 Topical application of antagonists of these receptors prevented these pathological changes. On the other hand, topical application of agonists of chloride permeable receptors such as GABA(A) receptor or glycine receptor accelerated the barrier repair and prevented the epidermal hyperplasia 46... 

Denda, M., Tsuchiya, T., Hosoi, J., and Koyama, J. (1998) Immobilization-induced and crowded environment-induced stress delay barrier recovery in murine skin. Br. J. Dermatol. 138 780-785. 

Denda, M., Kitamura, K., Elias, P.M., and Feingold, K.R. (1997) 7>ares -4-(aminomethyl) cyclohexane carboxylic acid (T-AMCHA), an anti-fibrinolytic agent, accelerates barrier recovery and prevents the epidermal hyperplasia induced by epidermal injury in hairless mice and humans. J. Invest. Dermatol. 109 84-90. 

Denda, M., Inoue, K., Inomata, S., and Denda, S. (2002) GABA (A) receptor agonists accelerate cutaneous barrier recovery and prevent epidermal hyperplasia induced by barrier disruption. J. Invest. Dermatol. 119 1041-1047. 

Zettersten, E.M., Ghadially, R., Feingold, K.R., Crumrine, D., and Elias, P.M., Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronologically aged skin, J. Am. Acad. Dermatol., 37, 403 108, 1997. 

Loden, M., Barrier recovery and influence of irritant stimuli in skin treated with a moisturizing cream. Contact Dermatitis, 1997, 36 256-60. 

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. 

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. 

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. 

Effects of Neurotransmitter Receptor Agonists and Antagonists on Skin Permeability Barrier Recovery... 

FIGURE 15.1 Topical application of serotonin (5HTA) receptor agonist or melatonin accelerates skin barrier recovery after barrier disruption. 

We previously demonstrated that application of a negative electric potential on the skin surface affects the ion gradient in the epidermis and accelerates lamellar body secretion and skin barrier recovery.7... 

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). 

Barium sulfate is a stable inorganic material that has been used for contrast media or cosmetic products because of its stability. Since a negative external electric potential accelerates skin barrier repair after barrier disruption, we hypothesized that topical application of barium sulfate would affect the skin barrier recovery rate, depending on the f potential. 

FIGURE 15.3 Correlation between the barrier recovery 2 h after tape stripping and the f potential of barium sulfate. There is a significant correlation between the barrier recovery rate and f potential. 

FIGURE 15.4 Scanning electron microscopic observation of two different forms of barium sulfate. In (a) flat board structures are observed (bar = 20 /im). This type has a negative f -potential and accelerates skin barrier recovery, (b) shows disordered structure (bar = 20 gm). This type has a positive potential and does not accelerate barrier repair. 

Fuziwara, S., Ogawa, K., Aso, D., Yoshizawa, D., Takata, S. and Denda, M., Barium sulfate with a negative f potential accelerates skin permeable barrier recovery and prevents epidermal hyperplasia indueced by barrier disruption. Br. J. Dermarol. 151 557-564, 2004. 

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... 

Fluhr, J.W. et al., Impact of anatomical location on barrier recovery, surface pH and stratum corneum hydration after acute barrier disruption, Br. J. Dermatol., 146, 770, 2002. 

Mauro, T.M. et al., Barrier recovery is impeded at neutral pH, independent of ionic effects implications for extracellular lipid processing, Arch. Dermatol. Res., 290, 215,1998. 

Hara, M., Ma, T., and Verkman, A. Selectively reduced glycerol in skin of Aquaporin-3-deficient mice may account for impaired skin hydration, elasticity and barrier recovery,./. Biol. Chem., 277, 44616, 2002. 

In surfactant-damaged skin a 5% urea cream has been shown to promote barrier recovery.65,66 The acceleration in barrier recovery was mainly observed as a more rapid decrease in TEWL. Furthermore, a recent placebo-controlled study proved that urea was responsible for the accelerated barrier recovery... 

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