Yeon Kyung Kim

Effects of Infrared Radiation and Heat on Human Skin Aging in vivo

Sunlight damages human skin, resulting in a wrinkled appearance. Since natural sunlight is polychromatic, its ultimate effects on the human skin are the result of not only the action of each wavelength separately, but also interactions among the many wavelengths, including UV, visible light, and infrared (IR). In direct sunlight, the temperature of human skin rises to about 40 degrees C following the conversion of absorbed IR into heat. So far, our knowledge of the effects of IR radiation or heat on skin aging is limited. Recent work demonstrates that IR and heat exposure each induces cutaneous angiogenesis and inflammatory cellular infiltration, disrupts the dermal extracellular matrix by inducing matrix metalloproteinases, and alters dermal structural proteins, thereby adding to premature skin aging. This review provides a summary of current research on the effects of IR radiation and heat on aging in human skin in vivo.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 15-19; doi:10.1038/jidsymp.2009.7.

Changes in glycosaminoglycans and related proteoglycans in intrinsically aged human skin in vivo.

Abstract:  Glycosaminoglycans (GAGs) and proteoglycans (PGs) are involved in various structural functions and physiological regulations in the skin. To investigate the intrinsic ageing‐dependent GAG and PG changes and their gender‐specific difference, immunohistochemical stains of several GAGs and PGs were performed in sun‐protected buttock skin tissues of young and old, male and female (total n = 32) human skin. Stains of alcian blue, hyaluronic acid (HA) and heparan sulphate were reduced in aged skin in both genders, whereas chondroitin sulphate stain was decreased only in female. Stains of HA synthase‐2, CD44, CD44v3, syndecan‐1 and decorin were decreased in aged skin in both genders, whereas perlecan stain was reduced only in female, and syndecan‐4 stain did not change. Versican stain was increased in male aged skin, but not in female. Age‐ and gender‐related changes in GAGs and PGs in intrinsically aged buttock skin elucidated in this study may play important roles in intrinsic skin ageing process.

Intrinsic aging- and photoaging-dependent level changes of glycosaminoglycans and their correlation with water content in human skin

BACKGROUND Glycosaminoglycans (GAGs) have various structural and physiological regulatory functions in skin, including tissue water maintenance, due to their high water-holding capacity. OBJECTIVE To investigate changes of GAGs during intrinsic aging and photoaging of human skin and their correlations with water content. METHODS Samples of sun-protected buttock and sun-exposed forearm skin were obtained from young male (21-30 years, n=8) and female (20-33 years, n=8) subjects, as well as old male (70-78 years, n=8) and female (70-80 years, n=8) subjects, and their epidermal and dermal contents of hyaluronic acid (HA), total sulfated GAG (tsGAG), total uronic acid (tUA), and tissue water were measured. HA content was determined by enzyme-linked immunosorbent assay using HA-binding protein, tsGAG by the sulfated GAG assay kit using 1,9-dimethylmethylene blue, tUA by carbazole reaction, and tissue water by subtraction of tissue dry weight from wet weight. RESULTS In the buttock, HA was higher in dermis than in epidermis, while tsGAG and tUA were higher in epidermis. In intrinsically aged buttock, epidermal HA and dermal tsGAG and tUA decreased. However, when analyzed for each gender, epidermal tsGAG, tUA, and tissue water decreased only in females. Forearm/buttock ratios of each molecule were compared for determination of photoaging-dependent changes. Forearm/buttock ratios of HA, tsGAG, tUA, and tissue water increased in aged dermis, but showed no change in aged epidermis. When analyzed for each gender, ratios of epidermal HA and tissue water increased only in aged females, while ratios of epidermal tsGAG, tUA, and tissue water decreased only in aged males. Correlations of water content with HA, tsGAG, and tUA were found in epidermis, but not with tsGAG in dermis. CONCLUSION These intrinsic aging- and photoaging-dependent GAG changes and their correlations with water content provide new insights into the pathophysiology of dry skin in the elderly.

Increased expression of TRPV1 channel in intrinsically aged and photoaged human skin in vivo

Abstract:  Transient receptor potential vanilloid type 1 (TRPV1) is activated by various stimuli including capsaicin, heat and acid. While TRPV1 has been localized in the epidermis, little is known about the physiological role of TRPV1 in the skin, especially in skin ageing. In this study, we investigated the effect of acute UV irradiation on TRPV1 expression in human skin and the changes in TRPV1 mRNA and protein in intrinsic ageing and photoageing using human sun‐protected (upper inner arm) and sun‐exposed (forearm) skin of young and elderly subjects.

Heat-induced MMP-1 expression is mediated by TRPV1 through PKCα signaling in HaCaT cells

Background:  Matrix metalloproteinase‐1 (MMP‐1) is considered a key initiator of collagen degradation in inflammatory responses. A heat‐gated channel, transient receptor potential vanilloid type 1 (TRPV1), induces release of proinflammatory mediators. TRPV1 channels have been localized to the epidermis and we have recently suggested that they act as mediators of heat‐induced MMP‐1. The aim of this study was to investigate the signaling of TRPV1 in MMP‐1 regulation by heat shock in human epidermal keratinocytes.

Prevention of UV-induced skin damages by 11,14,17-eicosatrienoic acid in hairless mice in vivo.

Polyunsaturated fatty acids (PUFAs) are known to play important roles in various physiological and pathological processes. Recent studies have shown that some omega-3 (ω-3) PUFAs, such as eicosapentaenoic acid (EPA) and dodecahexaenoic acid (DHA), have protective effects on acute and chronic UV-induced changes. However, the effects of other ω-3 PUFAs including 11,14,17-eicosatrienoic acid (20:3) (ETA) on UV-induced skin damages are poorly understood. In this study, we investigated the cutaneous photoprotective effects of ETA in hairless mice in vivo. Female HR-1 hairless mice were topically treated with vehicle (ethanol:polyethylene glycol=30:70) only, 0.1% ETA, or 1% ETA once a day for 3 successive days after one time UV irradiation (200 mJ/cm2) on dorsal skins. Skin biopsy was carried out on the fourth day (72 hr after UV irradiation). We found that topical treatment with ETA attenuated UV-induced epidermal and dermal thickness and infiltration of inflammatory cells, and impairment of skin barrier function. In addition, ETA suppressed the expression of IL-1β, COX-2, and MMP-13 induced by UV irradiation. Our results show that the topical application of ETA protects against UV-induced skin damage in hairless mice and suggest that ETA can be a potential agent for preventing and/or treating UV-induced inflammation and photoaging.

UV decreases the synthesis of free fatty acids and triglycerides in the epidermis of human skin in vivo, contributing to development of skin photoaging

BACKGROUND Although fatty acids are known to be important in various skin functions, their roles on photoaging in human skin are poorly understood. OBJECTIVE We investigated the alteration of lipid metabolism in the epidermis by photoaging and acute UV irradiation in human skin. METHODS UV irradiated young volunteers (21-33 years, n=6) and elderly volunteers (70-75 years, n=7) skin samples were obtained by punch biopsy. Then the epidermis was separated from dermis and lipid metabolism was investigated. RESULTS We observed that the amounts of free fatty acids (FFA) and triglycerides (TG) in the epidermis of photoaged or acutely UV irradiated human skin were significantly decreased. The expressions of genes related to lipid synthesis, including acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), sterol regulatory element binding proteins (SREBPs), and peroxisome proliferator-activated receptors (PPARgamma) were also markedly decreased. To elucidate the significance of these changes of epidermal lipids in human skin, we investigated the effects of TG or various inhibitors for the enzymes involved in TG synthesis on the expression of matrix metalloproteinase-1 (MMP-1) in cultured human epidermal keratinocytes. We demonstrated that triolein (TG) reduced basal and UV-induced MMP-1 mRNA expression. In addition, each inhibitor for various lipid synthesis enzymes, such as TOFA (ACC inhibitor), cerulenin (FAS inhibitor) and trans-10, cis-12-CLA (SCD inhibitor), increased the MMP-1 expression significantly in a dose-dependent manner. We also demonstrated that triolein could inhibit cerulenin-induced MMP-1 expression. Furthermore, topical application of triolein (10%) significantly prevented UV-induced MMP-13, COX-2, and IL-1beta expression in hairless mice. CONCLUSION Our results suggest that TG and FFA may play important roles in photoaging of human skin.

UV Modulation of Subcutaneous Fat Metabolism

Adipose tissue is not a homogeneous organ. Visceral fat accumulation is associated with atherosclerosis and metabolic syndrome, but peripheral subcutaneous (SC) fat accumulation may be protective. Human skin is continuously exposed to UV light. UV can penetrate the epidermis and into the mid-dermis, but not into the SC fat tissue of human skin. However, we here show that SC fat tissue in chronically sun-damaged skin contains less fat than naturally aged skin, and even a single UV exposure of human skin reduced lipid synthesis in the underlying SC fat tissue through transcriptional regulation of the lipogenic enzymes, acetyl CoA carboxylase, fatty acid synthase, and stearoyl CoA desaturase, of their transcription activator sterol regulatory element-binding protein-1 (SREBP-1), and of two key adipogenic transcription factors, CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor γ. The cytokines IL-6, IL-8, monocyte chemoattractant protein-3 (MCP-3), and placenta growth factor, produced by keratinocytes and fibroblasts in response to UV, may be responsible for the reduction of SC fat, and these cytokines, except MCP-3, may act by upregulation of suppressor of cytokine signaling-3 expression. Our data demonstrate the inhibitory effects of UV light on SC lipid synthesis and provide proof of concept for targeting cytokines for SC fat tissue modification.

Chronic heat treatment causes skin wrinkle formation and oxidative damage in hairless mice.

We have previously demonstrated that heat shock could induce expression of matrix metalloproteinases (MMPs) in skin cells. These results implicated that chronic heat treatment may cause skin wrinkles. Therefore, in the present study, we investigated the effects of chronic heat treatment (43 °C, 30 min, 3 times/week, 6 weeks) on wrinkle formation in skin of hairless mice. We found that repetitive heat treatment induced skin wrinkles after a period of 6 weeks in skin of hairless mice. Histologically, heat treatment resulted in increased thickness of the epidermis and dermis. And repetitive heat treatment resulted in significantly increased expression of MMP-13 protein and mRNA, but not MMP-2 and -9, in skin of hairless mice. We also demonstrated that activities of antioxidant enzymes, catalase, and superoxide dismutase (SOD), were reduced by chronic heat treatment. In addition, oxidative damage was increased in skin of mice after chronic exposure to heat shock. Taken together, our results suggested that chronic exposure of the skin to heat can cause skin wrinkling. And, increase of MMP-13, decrease of antioxidant enzymes activity, and consequent oxidative damage by chronic heat treatment may play an important role in development of skin aging in hairless mice.

Myeloid Differentiation Factor 88 Regulates Basal and UV-Induced Expressions of IL-6 and MMP-1 in Human Epidermal Keratinocytes

Myeloid differentiation factor 88 (MyD88) is known as an adaptor protein for the Toll-like receptor (TLR) family and participates in signal transduction by binding to the cytoplasmic Toll/IL-1 receptor (TIR) domains of activated TLR. In this study, we demonstrated that expression of MyD88 is increased in photoaged skin compared with intrinsic aged human skin of the same elderly individuals, and that acute UV irradiation increases MyD88 expression in human skin in vivo. To investigate the effects of these high levels of MyD88 in photoaged skin and acutely UV-irradiated skin, human epidermal keratinocytes were infected with adenovirus expressing wild-type (MyD88wt), dominant-positive (MyD88DeltaC), and dominant-negative (MyD88DeltaN) MyD88 forms. Overexpression of MyD88wt and MyD88DeltaC, but not of MyD88DeltaN, increased the basal expressions of IL-6 and matrix metalloproteinase-1 (MMP-1) in human epidermal keratinocytes. Moreover, overexpression of MyD88DeltaN prevented UV-induced expressions of IL-6 and MMP-1 by inhibiting UV-induced activation of NF-kappaB and activating protein-1. These results suggest that MyD88 is important in IL-6 and MMP-1 expressions in both acutely UV-irradiated skin and in chronically sun-exposed human skin.