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.

• Equimolar distribution of the three key SC lipids

Whereas the above-described studies clearly demonstrate the individual requirement for Chol, FFA, and Cer for the permeability barrier, when these lipids are applied topically, they must be supplied in approximately equimolar proportions for normal barrier recovery to occur (Table 10.2). For example, topical applications of any one or two of the three key lipids to acutely perturbed skin actually delays barrier recovery (Table 10.2). Both incomplete and complete mixtures of the three key lipids rapidly traverse the SC, internalize within the granular cell layer, targeting the trans-Golgi network, where LB are formed (Fig. 10.4). Exogenous and endogenous lipids mix within nascent LB, producing normal or abnormal LB contents and derived lamellar membrane structures, depending on the molar distribution of the applied lipids. Barrier recovery can be further accelerated by increasing the proportion of any one of the three key lipids to a 3 : 1 : 1 ratio (Table 10.2 and Fig. 10.5). Thus, physiologic mixtures of topical lipids influence barrier function, not by partially occluding the SC, as do nonphysiologic lipids (see below), but rather by contributing to the epidermal lipid pool that is delivered to the SC interstices.

Table 10.2 Barrier recovery after various topical treatments

Fig. 10.4 Physiologic lipids traverse the stratum corneum, enter the nucleated cell layers, targeting the lamellar body secretory system

Fig. 10.5 Barrier repair accelerates (towards a ‘0’ abnormality), as the proportion of any one of the three key lipids increases towards (but not beyond) 3 : 1 : 1: (A) cholesterol; (B) ceramides.

(Reproduced with permission from Man MM, Feingold KR, Thornfeldt CR, Elias PM 1996 Optimization of physiological lipid mixtures for barrier repair. Journal of Investigative Dermatology 106:1096–1101)

NONPHYSIOLOGIC LIPIDS: MECHANISM OF ACTION

In contrast to physiologic lipids, classic nonphysiologic lipids, such as petrolatum, do not enter the lipid-secretory pathway of the granular cell, and, in fact, they do not penetrate beneath the SC. They do, however, fully infiltrate the extracellular domains of the SC, where they form a hydrophobic, nonlamellar phase that largely displaces the lamellar bilayers. These lipids, which include not only petrolatum, but also agents such as beeswax, lanolin, squalane, and a variety of other hydrocarbons, function largely as a vapor-permeable membrane, i.e. they reduce water loss immediately (Table 10.2) but not completely. In contrast, physiologic lipids display a lag time that reflects the time necessary for SC transport, endocytosis, secretion, and lamellar membrane formation (Table 10.2—compare petrolatum to physiologic lipids; Fig. 10.4). Nonphysiologic lipids have the further advantage that they do not discriminate among types of barrier abnormalities, and the same degree of correction is achieved, regardless of the nature of the barrier disturbances. Further, it should be noted that the nonphysiologic lipids, though not components of the lamellar membranes, in some cases display a host of other, potentially beneficial properties, including anti-inflammatory, hydrating, waterproofing, and insulating characteristics. Because of the fundamental differences in their mechanisms, the two classes of molecules are complementary in improving barrier function (e.g. Table 10.2—nonphysiologic plus physiologic).

RATIONALE FOR BARRIER REPAIR THERAPY

The contrasting features of nonphysiologic and physiologic lipids further dictate the clinical settings where each should be uniquely useful. While nonphysiologic lipids such as petrolatum function like vapor-permeable membranes at the surface of the SC, physiologic lipids augment or supplement the epidermis’s own lipid biosynthetic machinery. As noted above, many skin diseases are associated with barrier abnormalities, and other pathophysiologic insults, such as psychological stress or aging, can further aggravate these processes (Fig. 10.3). In some of these cases, e.g. psychological stress or glucocorticoid therapy, there is an equivalent, global reduction in lipid production. In others, e.g. aging and atopic dermatitis, the global reduction is aggravated by a further reduction in one of the three key species (see below).

Logically then, in these studies, bolstering epidermal barrier status should decrease susceptibility not only to these skin diseases, but also to others that are triggered, sustained, or exacerbated by external perturbations, most notably contact dermatitis and psoriasis (Fig. 10.6). In fact, in all skin disorders characterized by a barrier abnormality, the extent of the barrier abnormality parallels the extent of clinical severity, a further indication of the importance of the barrier abnormality for disease pathogenesis.

Fig. 10.6 Disease pathogenesis and barrier repair

DEPLOYMENT OF BARRIER REPAIR THERAPY

The recent emergence of ‘barrier repair’ therapy represents a set of pathophysiologically based strategies that should decrease the susceptibility to these and other disorders, characterized by barrier abnormalities. These repair approaches can be classified into three subcategories (Table 10.3):

Table 10.3 Logical barrier repair strategies—clinical indications

Modified from Elias PM, Feingold KR 2001 Does the tail wag the dog? Role of the barrier in the pathogenesis of inflammatory dermatoses and therapeutic implications. Archives of Dermatology 137:1079–1081

Nevertheless, all of these strategies have their appropriate use and clinical indications. In fact, we can now choose an appropriate barrier strategy for a specific clinical indication based upon knowledge of disease pathogenesis (Table 10.3). For example, atopic dermatitis (AD) is characterized by a global decrease in SC lipids with a steep reduction in ceramides attributable to increased sphingomyelin/glucosylceramide deacylase activity in affected epidermis. Hence, the logic, and recent apparent success, of a ceramide-dominant mixture of the three physiologic lipids as ancillary therapy in AD. In contrast, aged and photoaged epidermis exhibits a global reduction in SC lipids, with a further decrease in cholesterol synthesis—hence the success of a cholesterol-dominant mixture of physiologic lipids in this setting. So critical is the choice of a proper formulation that substitution of an FFA-dominant mixture for the cholesterol-dominant version drastically delays barrier recovery in aged skin (Table 10.4). Yet, there are several clinical situations where physiologic lipids might not be effective, if deployed alone, due to an impaired LB secretory system. These examples include radiation dermatitis (both UVB and x-irradiation), very premature infants (i.e. < 33 weeks), and perhaps the initial stages of wound healing. In such situations, nonphysiologic lipids or vapor-permeable dressing alone, with or without added physiologic lipids, would become the most logical choice.

Table 10.4 Effects of physiologic lipid mixtures on barrier recovery in young versus aged human skin

Physiologic lipids = free fatty acids, cholesterol, ceramides.

Modified from Zettersten EM, Ghadially R, Feingold KR, Crumrine D, Elias PM 1997 Optimal ratios of topical stratum corneum lipids improve barrier recovery in chronologically aged skin. Journal of the American Academy of Dermatology 37:403–408

SUMMARY

This chapter has addressed some of the new understandings regarding barrier function and the role of ceramides. The ideas are nicely summarized in Table 10.4 where the effects of physiologic lipid mixtures on barrier recovery in young versus aged skin are compared. Note that the relationship between the components of the intercellular lipids, consisting of fatty acids, ceramides, and cholesterol, may affect the ability of the skin to effect barrier repair. In contrast, ceramide-containing lipid mixtures represent an interesting cosmeceutical that may have an important role in atopic dermatitis (Table 10.3).