INTRODUCTION

Although the stratum corneum (SC) serves many defensive functions (Table 10.1), none is as important as its ability to prevent excess loss of fluids and electrolytes, i.e. the permeability barrier. Permeability barrier function is mediated by the organization of the extracellular lipids of the SC into a series of parallel lamellar membranes, which mediate not only permeability barrier function, but also additional, key protective functions of the epidermis (Fig. 10.1). The functions of the SC can be further localized to either the cellular (corneocyte) compartment or extracellular matrix (Table 10.1).

Table 10.1 Protective functions of mammalian stratum corneum

* Regulated by SC pH.

Fig. 10.1 Lamellar bodies deliver lipids and enzymes that mediate several key protective functions

DYNAMICS OF BARRIER RECOVERY

The skin barrier is assaulted frequently in daily life by hot water, detergents, solvents, mechanical trauma, and occupation-related chemicals. If these insults are frequently repeatedly and/or insufficiently repaired, they threaten the organism with desiccation due to accelerated transepidermal water loss (TEWL). To avoid this outcome, the underlying epidermis mounts a coordinated metabolic response, ranging from increased lipid synthesis to accelerated lipid secretion, aimed at rapidly restoring normal function. This response is elicited by any type of barrier insult (e.g. organic solvents, detergents, tape stripping) that depletes the SC of its complement of lipids. Although the total time required for barrier recovery varies according to age, there is an initial, rapid recovery phase that leads to 50–60% recovery in young humans in about 12 hours, with full recovery requiring about 3 days (Fig. 10.2). But in aged humans (> 75 years), complete recovery from comparable insults is prolonged to about 1 week. Restoration of barrier function is accompanied by reaccumulation of lipids, visible with either oil red O staining or Nile red fluorescence, and by the reappearance of membrane structures within the SC interstices, as early as 2 hours after acute disruption. Because artificial restoration of the barrier with vapor-impermeable membranes inhibits barrier recovery, as well as all of the metabolic processes linked to it, the entire metabolic response represents a response that is aimed specifically at restoring normal permeability barrier homeostasis.

Fig. 10.2 Cutaneous stress test (‘treadmill exam of the skin’) demonstrates the dynamic response of the epidermis to barrier disruption

CLINICAL APPLICATIONS OF THE CUTANEOUS STRESS TEST

The kinetics of barrier recovery after acute perturbations (also called the ‘cutaneous stress test’) can discern abnormal function or underlying pathology, even when basal parameters are normal (Fig. 10.2), analogous to the cardiac treadmill exam. Indeed, the cutaneous stress test reveals deficient barrier function both in aged and in neonatal skin, despite deceptively normal function in both age groups under basal conditions. Further, it amplifies differences between other ‘normal’ groups (Fig. 10.3):

Fig. 10.3 Cutaneous stress test has uncovered underlying barrier abnormalities in several settings. The barrier defect in these instances could exacerbate inflammatory skin diseases via amplification of the cytokine cascade

Finally, individuals subjected to increased psychological stress reveal a defect in barrier recovery, explaining the propensity for these factors to exacerbate inflammatory dermatoses, such as psoriasis and atopic dermatitis, which already display barrier abnormalities. We have proposed that these factors further amplify the cytokine cascade that characterizes these disorders (Fig. 10.3).

LIPID COMPOSITION OF LAMELLAR MEMBRANES

The extracellular lipids in the SC derive primarily from the secreted contents of epidermal lamellar bodies (LB), which are enriched in cholesterol, glucosylceramide, phospholipids, as well as their respective hydrolytic enzymes (Fig. 10.1). These lipid-processing enzymes catalyze the extracellular degradation of sphingomyelin and glucosylceramides to ceramides (Cer), and phospholipids to free fatty acids (FFA) that, along with cholesterol (Chol), form the lamellar membranes required for permeability barrier function. Thus, the SC lamellar membrane comprises unique biologic membranes that mediate the barrier because:

Together, these characteristics largely explain the barrier properties of the SC.

LIPID SYNTHESIS AND REQUIREMENTS FOR THE BARRIER

The formation of epidermal LB requires a coordinated synthesis of the major lipid components of LB, i.e. cholesterol, glucosylceramides, and phospholipids. Although the epidermis is a very active site of lipid synthesis even under basal conditions, permeability barrier disruption stimulates a further, marked increase in the synthesis of Chol, FFA, and Cer, which provides the pool of lipids that is required for the formation of new LB. However, synthesis of these lipids is not only regulated by barrier requirements, it is also required for normal function. Using specific inhibitors of key lipid synthetic enzymes, we demonstrated an individual requirement for Chol, FFA, Cer, and glucosylceramide synthesis for barrier formation. In fact, blockade of these enzymes always produces a similar result: decreased LB, as well as a paucity of extracellular lamellar membranes. Thus, each of the three key lipids is required individually for permeability barrier function.