One of the functions served by the epidermis in mammals is to form a barrier against excessive transcutaneous water loss to the environment. This barrier is formed by the anucleate, cornified, outermost layers of the epidermis, collectively known as the stratum corneum. Localized or generalized perturbations of the epidermal barrier occur in a variety of diseases and conditions of the skin and mucous membrane. These perturbations not only contribute significantly to the morphology of cutaneous lesions, but also activate certain skin diseases such as the Koebner phenomenon in psoriasis and the inflammation in eczematous disorders. The integrity of the barrier is also known to be a major factor in regulating epidermal DNA synthesis. Thus, maintenance of a normal epidermal barrier is a physiological means of inhibiting epidermal hyperproliferation. Examples of conditions that involve or give rise to a disrupted or dysfunctional epidermal barrier are:
fluid and electrolyte abnormalities, hypothermia, and infection through the skin in premature infants less than 33 weeks of gestational age; PA1 inflammation to mucous membranes, such as cheilitis, chapped lips, nasal irritation and vulvovaginitis; PA1 eczematous dermatitides, such as atopic and seborrheic dermatitis, allergic or irritant contact dermatitis, eczema craquelee, photoallergic dermatitis, phototoxic dermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis; PA1 ulcers and erosions resulting from trauma, burns, bullous disorders, or ischemia of the skin or mucous membranes; PA1 several forms of ichthyoses; PA1 epidermolysis bullosae; PA1 psoriasis; PA1 hypertrophic scars and keloids; PA1 cutaneous changes of intrinsic aging and photoaging; PA1 frictional blistering caused by mechanical shearing of the skin; and PA1 cutaneous atrophy resulting from the topical use of corticosteroids.
The key constituents of the epidermis that are needed for a functional barrier are the intercellular, lamellar bilayer sheets of stratum corneum lipids. The synthesis of stratum corneum lipids is relatively autonomous from circulating or dietary influences. The synthetic response is regulated instead by alterations in permeability barrier functions. The regulation occurs through changes in the activities, phosphorylation (activation) state, mass, and mRNA for the rate-limiting enzymes of each of the three key lipids: serine palmitoyl transferase (for ceramides), HMGCoA reductase (for cholesterol), and both acetyl CoA carboxylase and fatty acid synthase (for fatty acids). Other results of alterations in barrier function are the regulation of key enzymes of extracellular lipid processing. One such enzyme is .beta.-glucocerebrosidase, which catalyzes the conversion of precursor glycosylceramides into ceramides.
While permeability barrier requirements regulate lipid synthesis, the endogenous regulators of barrier development and homeostasis are not known. Recent studies from the inventors' laboratories have shown that several activators and ligands of the nuclear receptor superfamily, such as glucocorticoids, thyroid hormone, and estrogen, accelerate the appearance of a mature barrier in fetal rodent skin. Hanley, K., et al., "Epidermal barrier ontogenesis: maturation in serum-free media and acceleration by glucocorticoids and thyroid hormone but not selected growth factors," J. Invest. Dermatol. 106:404-411 (1996); Hanley, K., et al., "Hormonal basis for the gender difference in epidermal barrier formation in the fetal rat. Acceleration by estrogen and delay by androgen," J. Invest. Denmatol. 97:2576-2584 (1996). In contrast, other members of this family, such as 1,25-dihydroxy vitamin D.sub.3 9-cis-retinoic acid, and all-trans-retinoic acid, had no effect.
USPTO Backgrounds
USPTO Backgrounds