The skin is the largest organ of the body, accounting for about 15% of the total adult body weight. It performs many vital functions, including protection against external physical, chemical, and biologic assailants, as well as prevention of excess water loss from the body and a role in thermoregulation. The skin is continuous, with the mucous membranes lining the body’s surface (Kanitakis, 2002). The integumentary system is formed by the skin and its derivative structures (see Figure 1-1). The skin is composed of three layers: the epidermis, the dermis, and subcutaneous tissue (Kanitakis, 2002). The outermost level, the epidermis, consists of a specific constellation of cells known as keratinocytes, which function to synthesize keratin, a long, threadlike protein with a protective role. The middle layer, the dermis, is fundamentally made up of the fibrillar structural protein known as collagen. The dermis lies on the subcutaneous tissue, or panniculus, which contains small lobes of fat cells known as lipocytes. The thickness of these layers varies considerably, depending on the geographic location on the anatomy of the body. The eyelid, for example, has the thinnest layer of the epidermis, measuring less than 0.1 mm, whereas the palms and soles of the feet have the thickest epidermal layer, measuring approximately 1.5 mm. The dermis is thickest on the back, where it is 30–40 times as thick as the overlying epidermis (James, Berger, & Elston, 2006).

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Anatomy and Physiology of the Skin

Lipids and the epidermal permeability barrier

The primary function of the epidermis is to generate a protective sheath, the stratum corneum, that protects the organism from both desiccation and external assault.'-^ However, despite the stratum corneum's acknowledged importance, investigation of the cellular basis of its |X'rmeability has been hampered by extraordinary difficulties in its preservation for ultrastructural study. tJntil relatively recently, this layer was thought to be made of disorganized, desquamating cells, in which the barrier resided at the stratum corneum-stratum granulosum interface (stratum lucidum). But the elegant biophysi( al experiments of Blank and Scheuplein,-̂ -\"' together with the demonstration of the exquisite geometric organization of the stratum corneum,''-\"'' have Ix'stowed new respect on the stratum corneum, and have supjxirted the concept that the entire stratum corneum subserves the barrier function of the skin.^ Although the stratum corneum is very thin, it is remarkably tough and resilient.'-** Though highly impervious to water and most polar substances, lipid-soluble substances, depending upon their chain length, branching, saturation, and vehicle delivery system/ selectively traverse this layer. Because of its unique structure and composition, the stratum corneum has been particularly difficult to study uitrastructurally. Without the adequate morphologic data, btophysicists have understandably treated the stratum corneum as if it were a homogeneous film. Most have assumed that substances percolate across the stratum corneum without regard to potential cell membrane, cytoptasmic, or intercellular pathways.•*•\" Water-soluble substances have been presumed to traverse via keratin filaments, while lipid-soluble sub-

Epidermal Lipids, Membranes, and Keratinization.

The permeability barrier of the skin which prevents transcutaneous water loss and penetration of harmful drugs from the environment is localized in the horny layer of the epidermis. Multiple lipid bilayers obstructing the intercellular space of the stratum corneum fulfill this function. In contrast to cellular membranes consisting predominantly of phospholipids, these lamellae contain mostly ceramides, cholesterol and free fatty acids. The lamellae are derived from the contents of lamellar granules (LGs) which are synthesized in the viable epidermal layers by the keratinocytes. LGs display stacks of small disks each of which represents a flattened vesicle or liposome. Prior to terminal differentiation, the disks are exocytosed into the intercellular space and fused to form uninterrupted sheetlike lamellae. The singular lipid composition of LG-disks and of stratum corneum-lamellae reflects the multistage process of barrier formation. It also renders these structures well suited to provide for a barrier function.

The epidermal permeability barrier.

We show that connexin expression and in vivo patterns of communication were dramatically altered in response to epidermal wounding. Six hours after injury, Cx26 was up-regulated in the differentiated cells proximal to the wound, but was down-regulated in cells located at the wound edge. In contrast, Cx31.1 and Cx43 were down-regulated in cells both peripheral to and at the wounded edge. These patterns of altered connexin expression were detectable as early as 2 h after wounding and were most pronounced in 24-h old wounds. Increased expression of Cx26 was still evident in the hyperproliferative epidermis of 6-day old wounds. In vivo dye transfer experiments with Lucifer yellow and neurobiotin confirmed that junctional communication patterns were altered in ways consistent with changes in connexin expression. The data thus suggest that intercellular communication is intimately involved in regulating epidermal wound repair.

D. Peluchetti

Papers

The junctions of normal human epidermis: A freeze-fracture study