Peter Elias

..But antimicrobial peptide synthesis and delivery to the SC interstices accelerates after external insults to the barrier...

..Static models of the epidermis may not do justice to the ECM, which is metabolically active, as it changes both structure and function as it transits to the surface...

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..In this review we will assess emerging evidence that inflammation in AD results from inherited and acquired insults to the barrier and the therapeutic implications of this paradigm...

..Therapy based upon this new view of pathogenesis should emphasize approaches that correct the primary abnormality in barrier function, which drives downstream inflammation and allows unrestricted antigen access...

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..This cycle comprises an "outside-inside-outside" model of AD pathogenesis (Elias et al., in press)...

..We will review here emerging evidence that the inflammation in atopic dermatitis results from inherited and acquired insults to the barrier and the therapeutic implications of this new paradigm...

..The barrier abnormality provokes the clinical phenotype in these disorders not only by stimulating epidermal proliferation, but also by inducing inflammation...

..In contrast, "barrier repair" therapy, with a ceramide-dominant triple-lipid mixture of stratum corneum lipids, is more logical, of proven efficacy, and it provides a far-improved safety profile...

..We summarize evidence here that epidermal interfollicular pigmentation in early hominids likely evolved in response to stress to the permeability barrier...

..This article reviews emerging evidence that the inflammation in AD results from inherited and acquired insults to the barrier, as well as the therapeutic implications of this new paradigm...

..Together, these studies indicate that PPAR-beta/delta activation stimulates keratinocyte differentiation, is anti-inflammatory, improves barrier homeostasis, and stimulates TG accumulation in keratinocytes...

..These results demonstrate that LXR activators stimulate the formation of an acidic SC and improve both permeability barrier homeostasis and SC integrity/cohesion...

..These observations suggest that thiazolidindiones and perhaps other PPAR-gamma activators maybe useful in the treatment of cutaneous disorders...

..Because of its reproducibility, predictability, and low cost, this model could prove useful for evaluating both pathogenic mechanisms and potential therapies for AD...

..Thus, for plasma membrane localization in terminally differentiated keratinocytes, Na(+)/H(+) exchanger 1 requires an intact actin cytoskeleton, which is impaired in FAK-deficient cells...

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..Together, our data demonstrate that PPAR and LXR activators increase ABCA12 expression, providing an additional mechanism by which PPAR and LXR activators promote epidermal permeability barrier homeostasis...

..The ability of oxysterols to reverse epidermal hyperplasia suggests that these agents could be beneficial for the treatment of skin disorders associated with hyperproliferation and/or altered differentiation...

..The transient and incomplete nature of the developmental delay, however, is consistent with regulation of the late stages of epidermal development by multiple factors...

..These studies show marked pigment-type differences in epidermal structure and function that are pH driven...

..Since the liposensors are activated by endogenous lipid metabolites, they may serve as unique regulators of barrier homeostasis...

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..HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function...

..Second, the increase in SR-BI following barrier disruption suggests that SR-BI expression increases to facilitate cholesterol uptake leading to barrier restoration...

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..Together, these studies demonstrate that PPAR and LXR activators can prevent several of the adverse effects of topical GC on the epidermis...

..These results provide direct evidence for the "outside-inside" pathogenesis of AD and further suggest that maintenance of an acidic SC pH could prevent the emergence of AD in humans...

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..These abnormalities were normalized by exogenously acidifying the SC, suggesting a basis for the well-known acidification therapies that are widely used to treat the pathologic xerosis/eczema seen in moderately aged humans...

..But in contrast to lamellar ichthyosis, the CE scaffold partially normalizes in the outer SC in loricrin keratoderma...

..Finally, topical replenishment with epidermal physiologic lipids could represent a potential method to reduce the adverse cutaneous effects of both topical glucocorticoid treatment and Cushing's syndrome...

..Additionally, some of these activators exhibit potent antihyperplastic and anti-inflammatory activity in irritant contact dermatitis and acute allergic contact dermatitis murine models...

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..The delay in acidification of neonatal SC results in abnormalities in permeability barrier homeostasis and SC integrity and are likely due to pH-induced modulations in enzyme activity...

..005). CONCLUSIONS: A defective permeability barrier in children with ichthyosis can result in ample chronic losses of water and calories to impair growth...

..Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris...

..These studies suggest that topical treatment with epidermal physiologic lipids could be beneficial in stress-induced, barrier-associated dermatoses, such as psoriasis and atopic dermatitis...

..Hence, PPARalpha activators might be useful to prevent or treat certain common neonatal dermatoses...

..Thus, LXR and PPAR activators regulate the expression of SULT2B1b, the key enzyme in the synthesis of CS, which is a potent regulator of epidermal differentiation and corneocyte desquamation...

..In contrast, DRIP silencing had no apparent effect on these processes indicating that the two classes of coactivators are differentially utilized...

..These results show that sebaceous-gland-derived glycerol is a major contributor to stratum corneum hydration...

..Thus, full barrier competence appears to require the extension of acidification in microdomains from the SC/SG interface outward toward the skin surface in the immediate postnatal period...

..Our findings indicate that DGAT1 plays an important role in normal fur and sebaceous gland physiology and provide evidence that leptin modulates these processes in the skin...

..LXR activators could provide a new class of therapeutic agents for the treatment of cutaneous inflammatory disorders...

..Yet, while these new approaches hold great promise, if equally effective in human skin, they pose new questions about the risks of a highly permeabilized stratum corneum...

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..Thus, Cer → sphingosine → S1Pmetabolic conversion protects against UVB-induced, Cer-mediated apoptosis in keratinocytes, but excessive UVB overwhelms this mechanism, thereby leading to keratinocyte apoptosis...

..Barrier repair therapy can be effective in restoring normal function if a cholesterol-dominant mixture of the three key physiologic lipids, including ceramides and free fatty acids, is emphasized...

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..In conclusion, prolonged SC neutralization provokes profound abnormalities in SC function, due to pH-induced high SP activity that, in turn, degrades lipid processing enzymes and CD proteins...

..These results indicate that oxysterols induce specific AP-1 proteins, thereby activating involucrin, one of the genes required for epidermal differentiation...

..Thus, late differentiation-linked increases in FA2H expression are essential for epidermal permeability barrier homeostasis...

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..Together, these results further demonstrate that PPARbeta/delta in the epidermis: (1) is required for permeability barrier homeostasis; (2) regulates keratinocyte proliferation; and (3) modulates cutaneous inflammation...

..These studies demonstrate that (1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and (2) CRAMP is required for permeability barrier homeostasis...

..Conversely, the impaired acidification of neonatal SC, which has important functional and clinical consequences, can be explained by the relatively low activities of one or both of these mechanisms at birth...

..In this short review, we explore the ways in which the multiple defensive functions of the SC are linked and interrelated, either by their shared localization or by common biochemical processes...

..Because upregulation of mAGPAT mRNAs after tape-stripping could be partially reversed by artificial barrier restoration by occlusion, these studies suggest that an increase in the expression of AGPATs is linked to barrier requirements...

..These findings suggest that the functional mechanisms involving protein cross-linking that maintain the epidermal barrier and induce tissue repair are conserved across 700 million years of evolution...

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..Together, these results verify the utility of TEWL as a measure of permeability barrier status. Moreover, all tested instruments are reliable tools for the assessment of variations in permeability barrier function...

..The present study demonstrates that sudden changes from a high to a low humidity environment results in abnormal barrier function, which could adversely influence the incidence and/or severity of skin disorders...

..These studies provide a mechanistic basis for phenotypic variations in NS, and describe compensatory mechanisms that permit survival of NS patients in the face of unrelenting SP attack...

..These findings demonstrate that ELOVL4 is required for generating VLFA critical for epidermal barrier function, and that the lack of epidermal omega-O-acylceramides is incompatible with survival in a desiccating environment...

..Ikeyama and colleagues provide data that the nitric oxide signaling pathway also regulates barrier homeostasis...

..Finally, the clinical consequences and therapeutic implications of this integrated perspective are provided...

..However, since the metabolic fates of each pseudo-Cer remain unknown, their widespread deployment in topical agents has raised concern about potential toxicities...

..A functional consequence of this is that Elovl3-ablated mice exhibited a severe defect in water repulsion and increased trans-epidermal water loss...

..Because of their broad profile of beneficial effects on skin homeostasis, PPAR and LXR have great potential to serve as drug targets for common skin diseases such as psoriasis, atopic dermatitis, and skin cancer...

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..immunogenetic abnormalities for the development of disseminated viral infections in patients with AD. ..

..Then, we will explore how such pathway influence the three key functions. The information from these studies could lead to entirely new approaches to the therapy of common skin disorders. ..

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..These studies could lead to novel approaches to enhance transdermal drug delivery, potentially allowing whole new classes of formerly excluded compounds to access the internal environment...

..These studies should provide new strategies for the regulation of cutaneous barrier function that could result in novel forms of therapy for burn wounds, and improved delivery of topical drugs...

..Our research could point to straight-forward methods that could improve the health status of individuals at risk due to fair pigmentation, including veterans with atopic dermatitis and psoriasis. ..