My charge is to talk about some of the anatomic and physiologic aspects of the skin barriers. These are things that you either forgot the minute you left your residency or things you never knew.

Stratum corneum is a structurally and biochemically diverse area. We have a tendency to think of it just as dead cells, but the stratum corneum is extremely important. It's selectively permeable and protective against desiccation and also against environmental changes. It permits a small amount of water loss, and this is extremely important. This helps hydrate the outer layer of the stratum corneum, maintaining its flexibility and facilitating the stratum corneum maturation.

The stratum granulosum has lamellar granule formation and lipid precursor formation. There is also something called the conversion of filaggrin to natural moisturizing factor (NMF). This is an important part of how the stratum corneum functions.

What do we know about the stratum corneum? Phenotype and spatial arrangements of the corneocytes are very important. Its composition and extracellular lipids are extremely important. It has hydroscopic compounds, which allow water to come and go. It acts like a brick wall. It has lipids. Corneodesmosomes serve as the mortar and corneocytes as the brick wall.

Here you can see corneocytes, corneodesmosomes, and lipids serving as the mortar, and the bricks are shown. As you come up from the stratum corneum, up higher from the basal layer, you have keratin macrofibrils, which ultimately develop the NMF.

This is an electron micrograph. It shows how the corneocytes are "packaged": lipid, corneocyte, lipid, corneocyte, and corneodesmosome is the anchor.

The stratum corneum consists of a number of layers of corneocytes. They're relatively thin at 1 mcm, and they're about 1000 mcm² in terms of surface area. And the corneodesmosomes are extremely important in anchoring the corneocytes, and serve as the mortar for the stratum corneum.

Lipids are an extremely important part of this barrier function. Twenty percent of the stratum corneum volume is lipids. These appear as lamellar sheets and, by mass, about 50% of the lipids are ceramides, but also there are cholesterol and fatty acids. In the normal condition, phospholipids do not make up any important part of the lipid structure in the stratum corneum. Another interesting observation is about 100-150 mg of lipids are generated each day just in the normal process. So a fair amount of lipid turnover occurs.

Natural moisturizing factor is extremely important. This is a concept that I think is relatively new to the dermatologists. It's derived from filaggrin. It's unique to the stratum corneum. It's a mixture of low molecular weight molecules. They're water soluble and hygroscopic molecules and compounds, which allows you to take up and release water. The humectancy, the water binding capacity, is essential for the stratum corneum. It allows for enzymes to work in the corneodesmosomal degradation; it allows our skin cells, the stratum corneum cells, to be released. It's also important for its own production of NMF. Too much water is not good. Too little water is also not a good environment for the development of NMF.

What do we know about NMF? It declines with age. Electron micrograph studies show that there are decreased numbers of keratohyalin granules and, therefore, filaggrin exists in aged skin as well as senile xerosis. Actinic damaged skin contains less NMF. People who have a lot of photodamage have dry skin, and certainly this is part of it. Bathing also can decrease the production of NMF in the superficial layers of the stratum corneum, so too much water is just as bad as too little water in terms of the generation of NMF.

The stratum corneum is extremely active enzymatically, and these enzymes are important in hydrolyzing the corneodesmosomes so that stratum corneum cells can fall off. It's important for cross-linking cornified envelope proteins, as well as processing lipids. These enzymes also are extremely important in moving profilaggrin to filaggrin.

Water loss stimulates barrier repair and recovery. So desiccation of the stratum corneum is a stimulus for these enzymes to kick in and repair the system.

What factors affect barrier function? With age, there's a decline in the ability to restore the barrier. Also with age, there's a decline in the ability to make NMF. Race, disease, and diet also can affect this significantly. There's some evidence that stress may elevate glucocorticoid levels, and that may be an important part of the delay in this barrier recovery.

The winter months and the desiccating environment certainly affect barrier function and that includes decreased intracellular lipids. Cleansers and retinoids also have the ability to alter our barrier.

This schematic shows what happens when one has damaged barriers. In the upper left, is an alteration in the water flux, a change in ion distribution, but most important is the ability at the time of injury to induce cytokine release from the stratum corneum and from the epidermis. Epidermal injury can cause not only a release of interleukin-1, but probably other cytokines as well.

As a result of epidermal injury, one gets DNA synthesis and this synthesis is important in making new cells in the epidermis, ultimately leading to stratum corneum barrier repair with lamellar body secretion, and lipid secretion and biosynthesis. In addition, if this injury continues on, one may see hyperplasia of the epidermis and inflammation. Factors that may alter this a little are the severity of the damage, the predisposition of the individual, those who have sensitive skin, and environmental humidity.

What conditions are associated with barrier dysfunction? This is a very limited list, including atopic dermatitis, psoriasis, and winter and harsh weather.

With atopic dermatitis there's an alteration in barrier function. Sometimes the skin of these people feels rough, suggesting that there's already an alteration in the barrier and therefore the stratum corneum.

In terms of the stratum corneum and the barrier of atopics, a lot of inflammatory molecules play a role. An interesting aspect is that there's a decrease in the ceramide levels (the specific ceramide, ceramide [EOS], which contains ester-linked fatty acids, omega-OH fatty acids, and sphingosines, is common and important and heavily laden with linoleic acid), which normally occurs in the stratum corneum in patients with atopic dermatitis. This is altered primarily because the sphingomyelin deacylase affects the way these ceramides are metabolized and formed; as a result, one gets abnormal ceramide species.

Decreased numbers of keratohyalin granules, and therefore filaggrin, and ultimately decreased amounts of NMF are seen in people with atopic dermatitis. These abnormalities in ceramides and the keratohyalin granules, as well as scratching the skin, result in barrier dysfunction and loss of transepidermal water; hence there is a dry or xerotic feeling and diminished water-binding capacities.

Psoriasis is a proinflammatory event.

With psoriasis, there are dramatic changes in the stratum corneum lipid structure and composition, probably driven primarily by the inflammatory nature or the environment of patients with psoriasis. There is a perturbation of lipid delivery from lamellar bodies in the stratum corneum. Changes in ceramides, cholesterol, and fatty acids, the 3 most important lipids that exist in the stratum corneum, occur.

In addition, the epidermis is turning over at a very fast rate. Filaggrin synthesis also is abnormal and, hence, NMF production is altered. So the dryness, the desiccation, the xerosis that we associate with psoriasis are largely due to this abnormality in barrier function.

This means that transepidermal water loss is about 20 times that normally seen in patients without this disease. Therefore, you have decreased water-binding capacity.

What about dry skin? This is a picture of something I call "Chicago Winter Skin." We see people with tremendous amounts of xerosis. We see eczema. But this is a condition that I didn't see any other place but Chicago. These are somewhat, but not completely, perifollicular erythematous papules, some with scale. It looks like Grover's disease, but usually happens in the lower part of the trunk and on the flanks. When biopsied, one just sees a little bit of eczema or dermatitis within the epidermis and a perivascular inflammation, but not the changes of Grover's disease. We call this "Chicago Winter Skin" (winter xerosis).

We think it is induced by low humidity. Decreased external humidity in the environment can have some profound effects on the skin. Not too surprisingly, it reduces the stratum corneum water content, leading to reduced activity of the enzymes that are involved in normal keratinocyte maturation and desquamation. It also changes the ceramide biochemistry and structure. The lipids that we normally count on to be present in normal skin now are altered. There's a reduction in NMF. Therefore, the ability of the skin to retain water is altered. When one alters the water content, it also changes the enzymatic activity within the skin so that keratinocytes and corneocytes don't desquamate the same. Finally, there's the possibility that this can lead to cytokine production and inflammation. One of the things that I always found curious was the fact that people with dry skin could have erythema. How could that be? There's probably a cytokine profile or activity that induces this erythema andinflammation.

There's some evidence to show that if you live in a continuous dry environment, for example Arizona, it serves as a constant stimulus for a number of things. One is increased lamellar body formation and exocytosis. Remember, the lamellar bodies are where our lipids are formed. There's an alteration and an increase in stratum corneum layers as well as the stratum corneum lipids. Finally, a constant low dry environment is a greater stimulus for the production of more NMF, which is extremely important in terms of being able to hold water in the stratum corneum. As a result, people who live in a continuously dry environment have the ability to adapt better to winter weather than those who live in an intermittent humid environment.

For those of us who live where it's very humid in the summer and very dry in the winter, I think this is why we see this exaggeration in response.

I want to review a couple of important and salient features about normal stratum corneum. One, in the stratum granulosum there is lamellar body formation, which is the key to the formation of lipids. Keratohyalin granule formation and NMF precursors begin here.

In addition, with a series of events that are extremely important in enzymatic degradation, there is a conversion of filaggrin to NMF that we all count on to keep our skin not too moist and not too dry. Finally, we have a number of enzymatic steps that are extremely important, not only in helping move the epidermis along, but ultimately in the formation of an intact and well-organized stratum corneum.