George Man

Abnormal Epidermal Barrier Recovery in Uninvolved Skin Supports the Notion of an Epidermal Pathogenesis of Psoriasis

HHS Public Access Author manuscript Author Manuscript J Invest Dermatol. Author manuscript; available in PMC 2015 May 01. Published in final edited form as: J Invest Dermatol. 2014 November ; 134(11): 2843–2846. doi:10.1038/jid.2014.205. Abnormal Epidermal Barrier Recovery in Uninvolved Skin supports the Notion of an Epidermal Pathogenesis of Psoriasis Li Ye 1 , Chengzhi Lv 1 , George Man 2 , Shunpeng Song 1 , Peter M. Elias 2 , and Mao-Qiang Man 2 1 Dalian Skin Disease Hospital, Liaoning, P.R. China 2 Dermatology Author Manuscript Services, Veterans Affair Medical Center and University of California San Francisco, CA, USA Keywords Psoriasis; Stratum Corneum; Permeability Barrier; Hydration; pH; Transepidermal Water Loss To The Editor Author Manuscript Psoriasis is generally considered to be an immunologically-initiated disorder, which shares certain common susceptibility loci with autoimmune diseases (Zhang, 2012). Yet, both clinical experience (Gottlieb et al.,1990; Griffiths et al., 1995; Volden et al., 2001;) and recent molecular studies (Bergboer et al., 2012; Kim et al., 2011; Mischke et al., 1996; Vermeij et al., 2011) support an emerging concept that psoriasis could be ‘driven’ by a primary defect in epidermal permeability barrier function. Clinicians know well that psoriasis predictably flares during winter months (Park and Youn, 1998; Kwon et al., 2012), when the barrier is under additional stress due to low stratum corneum hydration, which accelerates transepidermal water loss (TEWL) rates (Lin, 2009; Muizzuddin et al., 2013). They also appreciate that sites vulnerable to epidermal trauma, such as the extensors of the extremities and the scalp, are preferentially involved in psoriasis. The Koebner phenomenon offers an additional, eloquent example of how psoriasis can be provoked by external perturbations. Finally, improvement of epidermal permeability barrier function by occlusion alone often alleviates psoriasis (e.g., Friedman, 1987). Author Manuscript Among psoriasis susceptibility genes, PSORS4 is located on chromosome 1q21, within the epidermal differentiation complex, which encodes numerous proteins required for epidermal differentiation and the formation of the cornified envelope (Mischke et al., 1996), a structure that is critical for the permeability barrier (Vermeij et al., 2011). Additionally, deletion of differentiation-related proteins, such as keratin1, whose levels are reduced in psoriasis (Thewes et al., 1991; Bata-Csorgo and Szell, 2012), not only compromises the permeability barrier, but also leads to upregulation of inflammatory genes and altered cytokine production Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms Address Correspondence To: Mao-Qiang Man, MD, Dermatology Service (190), 4150 Clement Street, San Francisco, CA 94121, USA, Tel: (415)750-2091, Fax: (415)750-2106, mqman@hotmail.com Or Chengzhi Lv, MD, dlpfb@126.com. All authors declare no conflicts of interest

Topical hesperidin prevents glucocorticoid-induced abnormalities in epidermal barrier function in murine skin.

Systemic and topical glucocorticoids (GC) can cause significant adverse effects not only on the dermis, but also on epidermal structure and function. In epidermis, a striking GC‐induced alteration in permeability barrier function occurs that can be attributed to an inhibition of epidermal mitogenesis, differentiation and lipid production. As prior studies in normal hairless mice demonstrated that topical applications of a flavonoid ingredient found in citrus, hesperidin, improve epidermal barrier function by stimulating epidermal proliferation and differentiation, we assessed here whether its topical applications could prevent GC‐induced changes in epidermal function in murine skin and the basis for such effects. When hairless mice were co‐treated topically with GC and 2% hesperidin twice‐daily for 9 days, hesperidin co‐applications prevented the expected GC‐induced impairments of epidermal permeability barrier homoeostasis and stratum corneum (SC) acidification. These preventive effects could be attributed to a significant increase in filaggrin expression, enhanced epidermal β‐glucocerebrosidase activity and accelerated lamellar bilayer maturation, the last two likely attributable to a hesperidin‐induced reduction in stratum corneum pH. Furthermore, co‐applications of hesperidin with GC largely prevented the expected GC‐induced inhibition of epidermal proliferation. Finally, topical hesperidin increased epidermal glutathione reductase mRNA expression, which could counteract multiple functional negative effects of GC on epidermis. Together, these results show that topical hesperidin prevents GC‐induced epidermal side effects by divergent mechanisms.

Epidermal Dysfunction Leads to an Age-Associated Increase in Levels of Serum Inflammatory Cytokines

Even though elderly populations lack visible or other clinical signs of inflammation, their serum cytokine and C-reactive protein levels typically are elevated. However, the origin of age-associated systemic inflammation is unknown. Our previous studies showed that abnormalities in epidermal function provoke cutaneous inflammation, and because intrinsically aged skin displays compromised permeability barrier homeostasis and reduced stratum corneum hydration, we hypothesized here that epidermal dysfunction could contribute to the elevations in serum cytokines in the elderly. Our results show first that acute disruption of the epidermal permeability barrier in young mice leads not only to a rapid increase in cutaneous cytokine mRNA expression but also an increase in serum cytokine levels. Second, cytokine levels in both the skin and serum increase in otherwise normal, aged mice (>12 months). Third, expression of tumor necrosis factor-α and amyloid A mRNA levels increased in the epidermis, but not in the liver, in parallel with a significant elevation in serum levels of cytokines. Fourth, disruption of the permeability barrier induced similar elevations in epidermal and serum cytokine levels in normal and athymic mice, suggesting that T cells play a negligible role in the elevations in cutaneous and serum inflammatory cytokines induced by epidermal dysfunction. Fifth, correction of epidermal function significantly reduced cytokine levels not only in the skin but also in the serum of aged mice. Together, these results indicate that the sustained abnormalities in epidermal function in chronologically aged skin contribute to the elevated serum levels of inflammatory cytokines, potentially predisposing the elderly to the subsequent development or exacerbation of chronic inflammatory disorders.

Heavy Cigarette Smokers in a Chinese Population Display a Compromised Permeability Barrier

Cigarette smoking is associated with various cutaneous disorders with defective permeability. Yet, whether cigarette smoking influences epidermal permeability barrier function is largely unknown. Here, we measured skin biophysical properties, including permeability barrier homeostasis, stratum corneum (SC) integrity, SC hydration, skin surface pH, and skin melanin/erythema index, in cigarette smokers. A total of 99 male volunteers were enrolled in this study. Smokers were categorized as light-to-moderate (<20 cigarettes/day) or heavy smokers (≥20 cigarettes/day). An MPA5 was used to measure SC hydration and skin melanin/erythema index on the dorsal hand, forehead, and cheek. Basal transepidermal water loss (TEWL) and barrier recovery rates were assessed on the forearm. A Skin-pH-Meter pH900 was used to measure skin surface pH. Our results showed that heavy cigarette smokers exhibited delayed barrier recovery after acute abrogation (1.02% ± 13.06 versus 16.48% ± 6.07), and barrier recovery rates correlated negatively with the number of daily cigarettes consumption (p = 0.0087). Changes in biophysical parameters in cigarette smokers varied with body sites. In conclusion, heavy cigarette smokers display compromised permeability barrier homeostasis, which could contribute, in part, to the increased prevalence of certain cutaneous disorders characterized by defective permeability. Thus, improving epidermal permeability barrier should be considered for heavy cigarette smokers.

Topical Hesperidin Enhances Epidermal Function in an Aged Murine Model

Author(s): Man, George; Mauro, Theodora M; Zhai, Yongjiao; Kim, Peggy L; Cheung, Carolyn; Hupe, Melanie; Crumrine, Debbie; Elias, Peter M; Man, Mao-Qiang

Commonly Employed African Neonatal Skin Care Products Compromise Epidermal Function in Mice

Neonatal mortality is much higher in the developing world than in developed countries. Infections are a major cause of neonatal death, particularly in preterm infants, in whom defective epidermal permeability barrier function facilitates transcutaneous pathogen invasion. The objective was to determine whether neonatal skin care products commonly used in Africa benefit or compromise epidermal functions in murine skin.

Therapeutic Benefits of Natural Ingredients for Atopic Dermatitis

Although a variety of regimens are available for the treatment of atopic dermatitis (AD), severe adverse reactions and unpopular costs often limit their usage. In contrast, certain inexpensive, naturally-occurring ingredients are proven effective for AD with fewer side effects. The beneficial effects of these ingredients can be attributed to inhibition of cytokine and chemokine expression, IgE production, inflammatory cell infiltration, histamine release, and/or the enhancement of epidermal permeability barrier function. Since herbal medicines are widely available, inexpensive and generally safe, they could be valuable alternatives for the treatment of AD, particularly for those patients who are not suitable for the utilization of immune modulators. In this review, we summarize the therapeutic benefits of natural ingredients for the treatment of AD and the mechanisms of their actions.