Does the Tail Wag the Dog?: Title and subTitle BreakRole of the Barrier in the Pathogenesis of Inflammatory Dermatoses and Therapeutic Implications

WE HAVE BEEN in the era of immunology in skin disease. Since the classic experiment of Schellander and Marks¹ describing epidermal hyperplasia following dermal implantations of carrageenan, the epidermal changes that accompany inflammatory dermatoses have been considered downstream participants in disease pathogenesis (inside-outside concept). Accordingly, the current paradigm calls for either nonspecific treatment of inflammation or therapy aimed at specific T-cell components.² Since the epidermal changes are considered mere downstream participants, therapies aimed at normalizing epidermal function are considered secondary and inconsequential. Despite the acknowledged importance of xerosis and epidermal injury in these diseases, recent consensus reports barely mention the use of emollients in the therapy of atopic dermatitis and psoriasis.^{3 - 5}

But the concept of the epidermis as a primary or essential participant in disease pathogenesis, like gossip in a darkened corridor, keeps reasserting itself!^{6 - 7} Dermatologists increasingly sense that the epidermal abnormality is not just a secondary phenomenon, but a critical, if not the primary, exacerbant of inflammatory skin disease. This reexamination follows logically from a renewed appreciation for the role of the stratum corneum (SC) in the provision of life at the interface with a hostile terrestrial environment. The SC is not merely an inert end product, but rather a sophisticated biosensor that responds to external perturbations, such as altered external humidity or external trauma. Thus, as the external humidity drops,⁸ or when the external surface of the skin is injured,⁹ a variety of signal cascades are initiated.^{6 - 7 ,9 - 11} Although these signals are still not fully characterized, the net positive result is stimulation of metabolic responses in the underlying epidermis aimed at normalizing SC function (Figure 1). When the newly generated and released signals remain restricted to the epidermis, such as occurs with modulations in ion gradients in the outer epidermis, the consequences may be entirely local. But some of these signals, for example, cytokines, growth factors, and a variety of lipid mediators, stimulate signal cascades that initiate not only epidermal homeostatic responses, but also inflammatory events in deeper skin layers. The best-known example of this sequence is the so-called cytokine cascade,^{6 - 7 ,11} which has been proposed to provoke or sustain several important inflammatory dermatoses (Table 1 in Schmuth et al¹² ). According to this outside-inside paradigm, the disease-specific components of the infiltrate, for example, the "abnormal T cells" in psoriasis and atopic dermatitis, are recruited downstream following either acute or sustained insults to the SC (Figure 2).

If correct, the outside-inside paradigm should stand muster to several predictions (Table 1): (1) The severity of disease phenotype should correlate with the extent of the epidermal abnormality. (2) Amelioration of the SC functional abnormality (eg, by occlusion alone) should reduce the inflammatory component of the disease. (3) Insults that are localized to the SC alone should suffice to initiate inflammatory skin disease. (4) Factors that modify disease prevalence or severity should affect SC barrier function (Figure 3). Table 1 provides several examples that are consistent with these predictions.

This issue of the ARCHIVES presents a more complex clinical example, initiated by both inside-outside and outside-inside mechanisms (Figure 4). Fractional ionizing radiation, aimed at breast tumors in deeper skin layers, induced a delayed permeability barrier abnormality that preceded and then accompanied evidence of clinical radiation dermatitis.¹² Moreover, the extent of the barrier abnormality was largely predictive of the severity of the subsequent dermatitis. While this interesting article did not address potential mechanisms, the authors did note the similarity of their findings to the effects of high doses of UV-B in a rodent model, where a delayed barrier abnormality also occurs.¹⁶ In the UV-B rodent model, the barrier abnormality has been attributed to the outward passage of a layer of secretion-incompetent (apoptotic?) keratinocytes through the outer epidermis.¹⁷ The delay in the onset of the barrier abnormality can be explained by the presence of sufficient pre-formed SC to maintain normal barrier function until the incompetent keratinocytes, which are unable to generate a functional barrier, replace the pre-formed SC.¹⁷ Normal function is restored quickly when new layers of secretion-competent SG cells, driven by compensatory hyperplasia,¹⁶ once again reach the SC.¹⁷ While acute UV-B injury produces the functional abnormality over a relatively narrow time window,¹⁶ Schmuth et al¹² show that fractional x-radiation produces cumulative effects within the nucleated cell layers that result in a more sustained barrier abnormality. In both situations, a faulty barrier would again, according to the outside-inside paradigm, initiate and sustain inflammation in underlying skin layers (Figure 3).

The therapeutic implications for irradiated skin seem obvious: treat not only the inflammation, but also restore and/or provide a temporary barrier. Hence, we now face the challenge of selecting the correct barrier repair strategy. Can similar standards of clinical therapeutics be applied to barrier repair therapies as are applied to drugs? Most importantly, can we identify the barrier preparation of choice, based on both the unique pathogenic features of each dermatosis and the putative mechanism of action of the barrier preparation? We suggest that it is possible to do so, at least in certain instances. For this discussion, we propose that barrier repair agents can be divided into the following 3 categories (Table 2): (1) dressings, (2) nonphysiologic lipids (eg, petrolatum jelly), and (3) physiologic lipids (ie, synthetic or naturally occurring SC lipids). Each of these categories can be further classified; for example, dressings can be either vapor permeable or vapor impermeable. Nonphysiologic lipids (eg, petrolum jelly or lanolin) constitute an extremely heterogeneous group, with highly variable types of activities. For this discussion physiologic lipids should comprise complete (3-component) mixtures of the 3 key SC lipids—cholesterol, ceramides, and free fatty acids—because incomplete mixtures actually impede barrier repair.^{18 - 19} Moreover, the 3-component mixture should be provided in an optimized (3:1:1) ratio, because these ratios have been shown to accelerate barrier repair.¹⁹

Having now identified specific categories of barrier repair preparations, can we now select the preferred agent(s) for a specific clinical indication, based on both current views of disease pathogenesis and knowledge of each agent's activity? The field of barrier repair therapeutics is still very much in its infancy; and indeed, very few studies have evaluated the clinical efficacy of barrier repair therapy. In Table 2, we attempted to couple examples of dermatoses with our opinion of the preferred or most logical choice of barrier therapy for that entity. Despite their near-universal application, the effective deployment of vapor-permeable dressings for wound healing and hypertrophic scars and/or keloids has been developed without awareness of the effect of these agents on barrier repair.²⁰ The demonstration that a nonphysiologic lipid-containing mixture (Eucerin; Beiersdorf AG, Hamburg, Germany) reduced the mortality-morbidity of low-birth-weight premature infants represents another instructive and logical application.²¹ Moreover, since fetal epidermis, younger than 34 weeks, does not yet possess a mature lamellar body secretory system and since physiologic lipids must be processed through a preexisting lamellar body secretory system, they might not be as effective as nonphysiologic lipids in extremely premature infants. Likewise, the group of x-irradiated patients described by Schmuth et al,¹² as well as recently sunburned patients, might be best served by a nonphysiologic lipid mixture. A barrier repair strategy, based on physiologic lipids alone, would likely be ineffective here again, because the barrier defect is linked to a dysfunctional lamellar body secretory system. In contrast, ceramide-dominant mixtures of physiologic lipids and cholesterol-dominant mixtures of physiologic lipids represent rational applications of these agents for atopic dermatitis²² and aging-photoaged epidermis,²³ respectively. Yet, we would like to emphasize that neither physiologic lipid mixtures nor nonphysiologic lipids or dressings have been subjected to rigorous, controlled studies for most of the putative indications listed in Table 2. Finally, neither the composition nor the barrier repair kinetics for most emollients are available to prescribing physicians.

This work was supported by grants AR19098 (Dr Elias), AR 39639 (Dr Feingold), AR 39448 (program project) (Drs Elias and Feingold), from the National Institutes of Health, Bethesda, Md, and the Medical Research Service, Department of Veterans Affairs, Washington, DC.

Mary C. Williams, MD, critically reviewed the manuscript. Sue Allen provided superb editorial assistance.