皱纹与皮肤光老化

皱纹是皮肤光老化的重要特点之一,临床上以皮肤粗糙,皱褶深大、不易平复为特征。从真皮病理改变、基底膜变化和真皮变化等组织学方面综述与光老化有关的皮肤皱纹的病理学改变,阐述皮肤光老化在皮肤皱纹形成中的作用。为进一步治疗和预防光老化皱纹提供依据和思路。     

Degenerative alterations of dermal collagen fiber bundles in photodamaged human skin and UV-irradiated hairless mouse skin: possible effect on decreasing skin mechanical properties and appearance of wrinkles

Dermal collagen fiber bundles (DCFB) are the major constructional element in the dermis. Although degenerative alterations of DCFB have been reported in chronologically aged skin, changes in photodamaged skin have not been fully investigated. We report ultrastructural alterations of DCFB, and their relation to skin elasticity using photodamaged human skin and UV-irradiated hairless mouse skin. The degree to which DCFB were intact and closely packed was evaluated and scored blindly. Exposed skin (outer forearm) exhibited marked ultrastructural degeneration. In UV-irradiated hairless mouse skin, the intact ultrastructural appearance of DCFB was gradually lost with increasing UV dosage; however, marked alterations in DCFB ultrastructure were absent in either human inner upper arm (unexposed) skin or nonirradiated age-matched control mouse skin. Skin mechanical properties were measured using a Cutometer SEM 474 suction extensometer, recording Ue* immediate deformation, Uv* viscous deformation, Uf* final deformation, and Ur* immediate contraction, all normalized for skin thickness. Uf*, Ue*, Uv*, and Ur/Uf were significantly decreased in exposed compared with unexposed skin. Significant positive correlations between degenerative alterations of DCFB and the decrease in Uf*, Ue*, and Uv* were seen. Changes of "% area of wrinkles" in UV-irradiated mouse skin was significantly correlated with degenerative changes of DCFB. Based on these results, we confirm observations made by others that chronic photodamage may have more severe effects on degeneration of DCFB than that of chronologic aging alone. Furthermore, degeneration of DCFB as detected ultrastructurally may, by its effect on skin elasticity, result in an increase in the appearance of wrinkles.     

Epidermal changes caused by chronic low-dose UV irradiation induce wrinkle formation in hairless mouse

To investigate the effects of chronic low-dose UV irradiation on the skin, hairless mice were irradiated with a 1/3 minimal erythemal dose (MED) of UV. We examined the relationship between visible changes and skin damage in the dermis and epidermis. Hairless mice were irradiated with UVB (20 mJ/cm2) and UVA (14 J/cm2) three times a week for 10 weeks, followed by a 24-week non-irradiation period. Visible fine wrinkling was present after 4 weeks of irradiation, and the wrinkling progressively worsened throughout the period of irradiation. The wrinkles remained after irradiation was discontinued. In dermal components, no significant histological changes in the collagen fibers and elastic fibers were found, and the amount of hydroxyproline was also not changed. Thus, in the epidermis, there was a significant increase in the number of stratum corneum layers and the terminal-differentiation marker, filaggrin, positive cells. The intensity of staining for the differentiation marker, keratin 1, was reduced. These changes were accompanied by wrinkle formation, and remained after discontinuance of irradiation. These findings suggested that chronic low-dose UV irradiation induces structural and quantitative changes in the epidermis as a result of keratinization impairment, and that this damage in the epidermis is an important causative factor in wrinkle formation.     

Fibrillin-rich microfibrils are reduced in photoaged skin. Distribution at the dermal-epidermal junction

Chronic sun exposure results in photoaged skin with deep coarse wrinkles and loss of elasticity. We have examined the distribution and abundance of fibrillin-rich microfibrils, key structural components of the elastic fiber network, in photoaged and photoprotected skin. Punch biopsies taken from photoaged forearm and from photoprotected hip and upper inner arm of 16 subjects with a clinical range of photoaging were examined for fibrillin-1 and fibrillin-2 expression and microfibril distribution. In situ hybridization revealed decreased fibrillin-1 mRNA but unchanged fibrillin-2 mRNA levels in severely photoaged forearm biopsies relative to photoprotected dermal sites. An immunohistochemical approach demonstrated that microfibrils at the dermal-epidermal junction were significantly reduced in moderate to severely photoaged forearm skin. Confocal microscopy revealed that the papillary dermal microfibrillar network was truncated and depleted in photoaged skin. These studies highlight that the fibrillin-rich microfibrillar network associated with the upper dermis undergoes extensive remodeling following solar irradiation. These changes may contribute to the clinical features of photoaging, such as wrinkle formation and loss of elasticity.     

Mechanics of wrinkle formation: micromechanical analysis of skin deformation during wrinkle formation in ultraviolet‐irradiated mice

Background/purpose: The mechanical aspects of wrinkle formation were studied in the dorsal skin of hairless mice. Methods: Wrinkles were induced by irradiating with ultraviolet (UV) B for 10 weeks, while observing skin deformation during wrinkle formation. Changes in skin dimensions were also observed during the specimen excision process. Wrinkle depth and interval were measured before and after removal of the cutaneous muscle layer. Local deformation of wrinkled skin during uniaxial stretch was also measured. Changes in curvature of skin specimens upon muscle layer removal were then observed to determine the force balance in skin layers. Results: The skin showed spontaneous contraction in response to UV irradiation. Wrinkled skin showed a marked decrease in the wrinkle depth and a slight increase in wrinkle interval following muscle layer removal, a peculiar mechanical response that cannot be explained by homogeneous deformation of the skin. This response was due to compressive deformations of dermal tissue caused by the muscle layer and concentrated at valleys of the wrinkles. Curvature measurements indicated that the muscle layer compressed the dermal tissue predominantly in the craniocaudal direction. Morphological observations showed that the wrinkles coincided with rows of pores and sulci cutis, where the structural stiffness of the horny layer was relatively low. The horny layer showed significant thickening. Conclusion: Taken together, we propose the following hypothetical mechanisms of wrinkle formation during UV irradiation: spontaneous contraction of the dermis while maintaining or increasing the epidermal area induces buckling of the epidermis into the dermis at mechanically weak lines, namely, the rows of pores and sulci cutis, and buckling may be amplified by the axial compression of the dermis by the muscle layer.     

Characteristics of skin wrinkling and dermal changes induced by repeated application of squalene monohydroperoxide to hairless mouse skin

We have studied the effect of squalene monohydroperoxides (Sq-OOH), initial products of UV-peroxidated squalene, on the skin of hairless mice. Repeated topical application of 10 mM Sq-OOH to hairless mice for 15 weeks induced definite skin wrinkling. When image analysis was used to compare wrinkle formation induced by ultraviolet B (UVB) irradiation and Sq-OOH treatment, the degree of wrinkling in exposed skin was seen to be similar. However, the characteristics of wrinkles induced by either method differed markedly with regard to direction and distribution. Biochemical analysis revealed a significant decrease in collagen content per unit area and mass in Sq-OOH-treated skin, whereas no changes per unit area and decrease in collagen per unit mass were observed in UVB-irradiated skin. As for glycosaminoglycan (GAG) content per unit area, significant increases were observed in both Sq-OOH-treated skin and UVB-irradiated skin. These changes were not induced by organic hydroperoxides such as TERT-butylhydroperoxide or cumene hydroperoxide treatment. Histological observation revealed epidermal hyperplasia and dermal alterations such as collagen degradation and GAG increases in Sq-OOH-treated skin. Histological changes induced by Sq-OOH were not as pronounced as those induced by UVB irradiation. These results clearly suggest that the wrinkling and changes in dermal collagen content induced by Sq-OOH are qualitatively different to those induced by UVB exposure. This may provide a useful model for the study of skin aging, particularly with regard to collagen content.     

Cutaneous photodamage in Koreans: influence of sex, sun exposure, smoking, and skin color

BACKGROUND: Severe wrinkles and pigmentary changes of the exposed skin indicate substantial damage due to UV radiation. Many investigators believe that the principal manifestation of photodamage in Asians is pigmentary change rather than wrinkles. However, to our knowledge, no well-designed study has investigated the characteristics of cutaneous photodamage in Asian skin. OBJECTIVE: To access the severity of wrinkles and dyspigmentation in Koreans exposed to sun and who smoked. METHODS: We developed new photographic scales for grading wrinkles and dyspigmentation in 407 Koreans to assess the severity of the wrinkles and dyspigmentation. We interviewed subjects to determine cumulative sun exposure and smoking history, and measured the skin color of individual subjects. RESULTS: Our photographic scales provided a reliable evaluation of photodamage severity in Koreans. The pattern of wrinkling in both sexes is similar, but women tended to have more severe wrinkles (prevalence odds ratio, 3.7). However, the pattern of dyspigmentation differed between the sexes. Seborrheic keratosis is the major pigmentary lesion in men, whereas hyperpigmented macules are the prominent features in women. Cigarette smoking is an independent risk factor for wrinkles, but not for dyspigmentation, in Koreans, and causes additive detrimental effects to wrinkles induced by aging and sun exposure. The constitutive skin color did not show any correlation with wrinkles or dyspigmentation. However, facultative pigmentation (sun exposure index) may reflect lifetime sun exposure, and it shows a good correlation with wrinkles in Koreans. CONCLUSION: Wrinkling is a major feature of photoaging in Koreans, as are pigmentary changes; smoking, sun exposure, and female sex are independent risk factors for wrinkles.     

From skin microrelief to wrinkles. An area ripe for investigation

Skin microrelief alters progressively with age. Wrinkles do not result from these changes but are superimposed upon them. Wrinkles result from structural changes in the epidermis, dermis and hypodermis. Four types of wrinkles can be recognized. Type 1 wrinkles are atrophic. Type 2 wrinkles are elastotic. Type 3 wrinkles are expressional. Type 4 wrinkles are gravitational. Each type of wrinkle is characterized by distinct microanatomical changes and each type of wrinkle develops in specific skin regions. Each is likely to respond differently to treatment. Skin microrelief and skin folds can be identified on histological examination. By contrast, only minimal dermal changes are found beneath permanent or reducible wrinkles compared with immediately adjacent skin. A series of objective and non-invasive methods is available to quantify the severity of wrinkling.     

Numbers of murine dermal mast cells remain unchanged during chronic ultraviolet B irradiation

Dermal mast cell numbers reportedly increase in response to chronic ultraviolet irradiation in both humans and in the HRS/Skh-1 mouse model of human photoaging. It has been hypothesized that these increased numbers of mast cells are responsible, at least in part, for the damage in this chronically irradiated or photoaged skin. However, few actual quantitative data have been reported to support this claim of increased dermal mast cell numbers caused by chronic ultraviolet irradiation. We sought to quantify the numbers of dermal mast cells in the skin of chronic ultraviolet-irradiated and control HRS/Skh-1 hairless mice. Dermal mast cells from irradiated and age-matched control mice were quantified by digital image analysis during a 20-week period of exposure to ultraviolet B (UVB) radiation. During the entire course of irradiation, there was no difference in the numbers of dermal mast cells between the irradiated and nonirradiated age-matched control mice. Visible physical evidence of the effects of chronic UVB irradiation, i.e., skin wrinkling, was evident after 6 weeks of treatment. The numbers of dermal mast cells in unirradiated age-matched NSA (CF-1) haired mice were three- to four-fold lower than those in either ultraviolet-exposed or unexposed HRS/Skh-1 mice. These findings indicate that dermal mast cell numbers in HRS/Skh-1 mice are not increased by chronic exposure to UVB radiation.     

Carbon dioxide laser treatment promotes repair of the three-dimensional network of elastic fibres in rat skin

BACKGROUND: We have previously reported that ultraviolet (UV) B irradiation induces a loss of linearity in the three-dimensional structure of dermal elastic fibres, which results in the reduction of elastic properties of the skin and leads to wrinkle formation. We further reported that repair of wrinkles by all-trans retinoic acid is accompanied by recovery of the linearity of elastic fibres. Carbon dioxide (CO2) lasers are widely used for treating wrinkles in cosmetic surgery. OBJECTIVES: To perform CO2 laser treatment of wrinkles induced in rat skin by UVB irradiation and to evaluate changes in the three-dimensional structure of dermal elastic fibres during wrinkle repair. METHODS: Wrinkles were induced in the hind limb skin of Sprague-Dawley rats by UVB irradiation (130 mJ cm-2 three times weekly for 6 weeks), followed by CO2 laser treatment (11.3 J cm-2). The surface appearance of the skin was evaluated by replica observation 6 and 10 weeks after CO2 laser treatment followed by measurement of mechanical properties using a Cutometer. Subsequently, perfusion fixation and digestion with formic acid were performed and elastic fibres were observed by scanning electron microscopy (SEM). Image analysis of SEM micrographs was carried out to evaluate the linearity in the three-dimensional structure of elastic fibres. RESULTS: Six weeks after CO2 laser treatment, all parameters of skin mechanical properties in the UVB-irradiated group recovered to levels of the control non-irradiated group, accompanied by repair of wrinkles and a significant increase in linearity of the three-dimensional structure of elastic fibres. CONCLUSIONS: These findings indicate that CO2 laser treatment has a therapeutic potential to repair wrinkles to non-irradiated levels through recovery of the three-dimensional structure of elastic fibres.     

Fermentable metabolite of Zymomonas mobilis controls collagen reduction in photoaging skin by improving TGF-beta/Smad signaling suppression

Solar ultraviolet (UV) irradiation causes damages on human skin and premature skin aging (photoaging). UV-induced reduction of type I collagen in dermis is widely considered primarily induction of wrinkled appearance of photoaging skin. Type I procollagen synthesis is reduced under UV irradiation by blocking transforming growth factor-beta (TGF-beta)/Smad signaling; more specifically, it is down-regulation of TGF-beta type II receptor (T beta RII). Therefore, preventing UV-induced loss of T beta RII results decreased type I collagen reduction in photoaging skin. Zymomonas mobilis is an alcohol fermentable, gram-negative facultative anaerobic bacterium whose effect on skin tissue is scarcely studied. We investigated the protective effects of fermentable metabolite of Z. mobilis (FM of Z. mobilis) against reduction of type I procollagen synthesis of UV-induced down-regulation of T beta RII in human dermal fibroblasts FM of Z. mobilis was obtained from lyophilization of bacterium culture supernatant. The levels of T beta RII and type I procollagen mRNA in human dermal fibroblasts were measured by quantitative real-time RT-PCR, and T beta RII protein levels were assayed by western blotting. T beta RII, type I procollagen, and type I collagen proteins in human dermal fibroblasts or hairless mouse skin were detected by immunostaining. FM of Z. mobilis inhibited down regulation of T beta RII mRNA, and protein levels in UVB irradiated human dermal fibroblasts consequently recover reduced type I procollagen synthesis. These results indicate UVB irradiation inhibits type I procollagen synthesis by suppression of TGF-beta/Smad signaling pathway, and FM of Z. mobilis has inhibitory effect on UVB-induced reduction of type I procollagen synthesis. While short period UVB irradiation decreased both T beta RII and type I procollagen protein levels in hairless mouse skin, topical application of FM of Z. mobilis prevented this decrease. Wrinkle formation in hairless mouse skin surface was accelerated by continuous 5 month UVB irradiation along with a reduction of type I collagen in the dermis, but this change was prevented by topical application of FM of Z. mobilis. From this experimental data, it is suggested that FM of Z. mobilis is effective for suppression of wrinkle formation in photoaging skin by inhibition of type I procollagen synthesis reduction.     

Effect of pre-treatment of almond oil on ultraviolet B-induced cutaneous photoaging in mice

Background Ultraviolet (UV) radiation has been implicated in photoaging and various types of skin carcinomas. Although the human skin has evolved several defense mechanisms to survive the insults of actinic damage like keratinization, melanin pigmentation, etc., it is still subjected to the harmful effects of sunlight. Aims In this study, the role of almond oil in reducing the degradative changes induced in skin upon exposure to UV radiation was investigated. Methods Mice were divided in four groups of 20 animals. Group I was the control group. Group II was negative control, which received almond oil treatment alone. Group III was exposed to UV radiation only and Group IV received both UV treatment and almond oil treatment. Visible skin grading assessed the changes based on a rating scale, biochemical tests (glutathione estimation and lipid peroxidation), and histopathologic studies. Results Upon exposure of mice to UV radiation, it was found that pronounced visible skin changes were seen after 12 weeks of exposure. The results of the biochemical tests, glutathione estimation, and lipid peroxidation showed that almond oil reduced the effect of UV light–induced photoaging on the skin. Histopathologic studies also indicated a photoprotective effect of almond oil on the skin after UV exposure. Conclusions It was concluded that topical almond oil is capable of preventing the structural damage caused by UV irradiation and it was also found useful in decelerating the photoaging process.     

In the shadow of the wrinkle: experimental models

Research on aging has run for decades, and knowledge on the biologic process of skin chronological and photoaging is still increasing thanks to read across results generated between human, animal, and in vitro studies. However, wrinkles should not be considered to result only from the aging process. There are few reports on specific wrinkle histological features compared to the surrounding skin, and there is thus a need in really wrinkling skin animal and in vitro models. UV-irradiated Hr mouse is a good model because it develops wrinkles. Nevertheless, as mouse skin is somehow different from human skin, the innovative model of wrinkling human skin xenograft on SCID mice seems to be really promising. Concerning in vitro and ex vivo models, although there have been considerable advances in reconstructing realistic aged skins, there is still a lack of in vitro wrinkling skin model, and unfortunately, this gap will probably be difficult to fill.     

Retinoic acids promote the repair of the dermal damage and the effacement of wrinkles in the UVB-irradiated hairless mouse

Chronic irradiation of hairless mice with UVB leads to elastosis as evidenced by both histologic means and an increase in skin desmosine content. Treatment with topical all-trans- or 13-cis-retinoic acid causes dose-dependent increments in the area of the dermal "repair zone"; skin desmosine content increases during irradiation but does not change significantly after irradiation is discontinued and retinoic acid treatment commenced. During the course of the irradiation the animals develop permanent wrinkles on the exposed dorsal surface, which can be recorded in plastic impressions. The extent of wrinkling can be quantitated and it has been demonstrated that topically applied retinoic acids lead to the complete effacement of these surface features and that the process appears to be permanent.     

Rolle der extrazellul?ren Matrix bei der extrinsischen Hautalterung

Photoaged skin is clinically characterized by wrinkling, laxity and a leather-like appearance. These symptoms of actinic aging are causally connected to histological and ultrastructural changes of the connective tissue of the dermis. Changes include both enzymatic degradation and reduced de novo synthesis of collagen which cause premature wrinkling of the skin. Changes in the hyaluronan and proteoglycan matrix lead to reduced water content and thereby increased laxity of the skin. Furthermore, the UV-induced remodeling of the extracellular matrix strongly affects the cellular phenotypes such as the regenerative capacity of dermal fibroblasts. In recent years considerable progress has been made towards the understanding of molecular and cellular mechanisms underlying the UV-induced changes of the extracellular matrix. Current findings in this field reveal interesting insights in the dermal aging and provide new targets and strategies for the treatment of photoaging.     

Protective role of adipose-derived stem cells and their soluble factors in photoaging

As individuals age, the skin undergoes changes, such as irregular pigmentation, thinning and loss of elasticity, that are due to both genetic and environmental factors. These changes may worsen, progressing to precancerous and cancerous diseases. Various medical treatments and topical cosmeceuticals have been used to treat some symptoms of photoaging, however, the results have been less than satisfactory. Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue, adipose-derived stem cells (ADSCs), display multi-lineage developmental plasticity and secrete various growth factors that control and manage the damaged neighboring cells. Recently, the production and secretion of growth factors has been reported as an essential function of ADSCs, and diverse regenerative effects of ADSCs have been demonstrated in the skin. For example, conditioned medium from ADSCs (ADSC-CM) stimulated both collagen synthesis and migration of dermal fibroblasts, which improved the wrinkling and accelerated wound healing in animal models. ADSC-CM also inhibited melanogenesis in B16 melanoma cells, and protected dermal fibroblasts from oxidative stress induced by chemicals and UVB irradiation. Therefore, ADSCs and soluble factors show promise for the treatment of photoaging, and this review introduces recent research developments of the ADSCs and ADSC-derived secretory factors regarding this issue.     

无创性检测技术在皮肤光老化中的应用

光老化是指皮肤长期受紫外线(ultraviolet,UV)辐射所引起的皮肤老化.光老化皮肤主要表现为毛细血管扩张、粗糙干燥、松弛、皱纹加深、色素沉着,甚至可能出现各种良性或恶性肿瘤.大量研究对光老化皮肤的变化从各个方面进行描述和评估,如临床肉眼评估、组织病理及免疫组织化学检查等.随着科技的发展,无创检测技术在皮肤光老化...     

Possible involvement of gelatinases in basement membrane damage and wrinkle formation in chronically ultraviolet B-exposed hairless mouse

A number of studies indicate that matrix metalloproteinase might be involved in photoaging, but little is known about their direct contribution to ultraviolet-induced histologic and morphologic changes in the skin in vivo. This study reports the relationship between changes of matrix metalloproteinase activities and ultraviolet B-induced skin changes in hairless mouse. The role of matrix metalloproteinase in the skin changes was studied by topical application of a specific matrix metalloproteinase inhibitor. The backs of mice were exposed to ultraviolet B three times a week for 10 wk. Histologic studies showed that the basement membrane structure was damaged, with epidermal hyperplasia, in the first 2 wk of ultraviolet B irradiation, followed by the appearance of wrinkles, which gradually extended in the latter half of the ultraviolet B irradiation period. We observed enhancement of type IV collagen degradation activity, but not collagenase or matrix metalloproteinase-3 activity, in extracts of ultraviolet B-irradiated, wrinkle-bearing skin. Gelatin zymographic analysis revealed that gelatinases, matrix metalloproteinase-9 and matrix metalloproteinase-2, were significantly increased in the extract. In situ zymographic study clarified that the activity was specifically localized in whole epidermis of ultraviolet B-irradiated, wrinkled skin in comparison with normal skin. The activity was induced around the basal layer of the epidermis by a single ultraviolet exposure of at least one minimal erythema dose. Furthermore, topical application of a specific matrix metalloproteinase inhibitor, CGS27023A, inhibited ultraviolet B-induced gelatinase activity in the epidermis, and its repeated application prevented ultraviolet B-induced damage to the basement membrane, as well as epidermal hyperplasia and dermal collagen degradation. Ultraviolet B-induced wrinkles were also prevented by administration of the inhibitor. These results, taken together, suggest that ultraviolet B-induced enhancement of gelatinase activity in the skin contributes to wrinkle formation through the destruction of basement membrane structure and dermal collagen in chronically ultraviolet B-exposed hairless mouse, and thus topical application of matrix metalloproteinase inhibitors may be an effective way to prevent ultraviolet B-induced wrinkle formation.     

Marked improvement induced in photoaged skin of hairless mouse by ER36009, a novel RARgamma-specific retinoid, but not by ER35794, an RXR-selective agonist

BACKGROUND: Photoaging (premature skin aging) results largely from repeated exposure of the skin to ultraviolet (UV) radiation from the sun. Topical all-trans retinoic acid (RA), the only agent that has been approved for the treatment of photoaging, has been shown to reverse this process. In this study, we evaluated the pharmacologic effects of novel synthetic retinoids, ER36009 and ER35794, on murine wrinkles induced by UVB. ER36009 is a specific agonist of retinoic acid receptor (RAR)gamma, the most abundant RAR subtype in the skin, while ER35794 is a potent retinoid X receptor (RXR)-selective agonist. METHOD: After a 10-week exposure to escalating doses of UVB irradiation, the animals were treated three times per week with ER36009 (0.0001%, 0.00025%, 0.0005%), ER35794 (0.025%, 0.05%, 0.1%), RA (0.05%) or acetone (control) for 3 weeks. RESULTS: ER36009 exerted a dose-dependent wrinkle-effacing effect, and 0.0005% ER36009-treated skin was significantly different from the control. ER36009 also significantly and dose-dependently increased both epidermal thickness and the area of the dermal repair zone defined by newly synthesized collagen. The effect of 0.0005% ER36009 on photodamaged skin was superior to that of 0.05% RA. In contrast, ER35794 was inactive in this model, though this compound exhibited lower local toxicity than other retinoids. CONCLUSIONS: These data indicate that RARgamma, but not RXR, plays an important role in the improvement of the signs of photoaging, and so a specific RARgamma agonist might be superior to an RAR pan-agonist for clinical treatment. We conclude that ER36009 is a candidate for a potent anti-skin-aging agent.