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. (+info)
Singlet oxygen mediates the UVA-induced generation of the photoaging-associated mitochondrial common deletion.
Mutations of mitochondrial (mt) DNA accumulate during normal aging. The most frequent mutation is a 4,977-base pair deletion also called the common deletion, which is increased in photoaged skin. Oxidative stress may play a major role in the generation of large scale mtDNA deletions, but direct proof for this has been elusive. We therefore assessed whether the common deletion can be generated in vitro through UV irradiation and whether reactive oxygen species are involved in this process. Normal human fibroblasts were repetitively exposed to sublethal doses of UVA radiation and assayed for the common deletion employing a semiquantitative polymerase chain reaction technique. There was a time/dose-dependent generation of the common deletion, attributable to the generation of singlet oxygen, since the common deletion was diminished when irradiating in the presence of singlet oxygen quenchers, but increased when enhancing singlet oxygen half-life by deuterium oxide. The induction of the common deletion by UVA irradiation was mimicked by treatment of unirradiated cells with singlet oxygen produced by the thermodecomposition of an endoperoxide. These studies provide evidence for the involvement of reactive oxygen species in the generation of aging-associated mtDNA lesions in human cells and indicate a previously unrecognized role of singlet oxygen in photoaging of human skin. (+info)
The effects of radicals compared with UVB as initiating species for the induction of chronic cutaneous photodamage.
There is substantial evidence that ultraviolet radiation induces the formation of reactive oxygen species which are implicated as toxic intermediates in the pathogenesis of photoaging. The aim of this study was to determine whether repeated topical treatment with benzoyl peroxide, a source of free radicals, produced the same cutaneous effects as chronic ultraviolet B radiation. Three concentrations of benzoyl peroxide (0.1, 1.5, 5.0% wt/wt) and three cumulative fluences of ultraviolet B radiation (0.9, 2.2, 5.1 J per cm2) used alone and in all combinations along with appropriate controls. Female SKH1 (hr/hr) albino hairless mice were treated 5 d per wk for 12 wk. Extracellular matrix molecules and histologic parameters were assessed. Ultraviolet B radiation induced a fluence-dependent and time-dependent increase in skin-fold thickness. Fluence dependence was seen for epidermal thickness, sunburn cell numbers, dermal thickness, glycosaminoglycan content, mast cell numbers, and skin-fold thickness. Benzoyl peroxide treatment alone caused less marked increases in epidermal and dermal measures compared with ultraviolet B under the conditions used. A benzoyl peroxide concentration-dependent increase was only observed for elastin content, although the highest concentration of benzoyl peroxide increased epidermal thickness and glycosaminoglycan content. A synergistic interaction between ultraviolet B and benzoyl peroxide was not found. These results indicate that repeated administration of benzoyl peroxide produces skin changes in the hairless mouse that qualitatively resemble those produced by ultraviolet B and suggest that common mechanisms may be involved. In addition, any potential synergistic effect of ultraviolet B and benzoyl peroxide was below the level of detection used in this study. (+info)
Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin.
Damage to human skin due to ultraviolet light from the sun (photoaging) and damage occurring as a consequence of the passage of time (chronologic or natural aging) are considered to be distinct entities. Photoaging is caused in part by damage to skin connective tissue by increased elaboration of collagen-degrading matrix metalloproteinases, and by reduced collagen synthesis. As matrix metalloproteinase levels are known to rise in fibroblasts as a function of age, and as oxidant stress is believed to underlie changes associated with both photoaging and natural aging, we determined whether natural skin aging, like photoaging, gives rise to increased matrix metalloproteinases and reduced collagen synthesis. In addition, we determined whether topical vitamin A (retinol) could stimulate new collagen deposition in sun-protected aged skin, as it does in photoaged skin. Sun-protected skin samples were obtained from 72 individuals in four age groups: 18-29 y, 30-59 y, 60-79 y, and 80+ y. Histologic and cellular markers of connective tissue abnormalities were significantly elevated in the 60-79 y and 80+ y groups, compared with the two younger age groups. Increased matrix metalloproteinase levels and decreased collagen synthesis/expression were associated with this connective tissue damage. In a separate group of 53 individuals (80+ y of age), topical application of 1% vitamin A for 7 d increased fibroblast growth and collagen synthesis, and concomitantly reduced the levels of matrix-degrading matrix metalloproteinases. Our findings indicate that naturally aged, sun-protected skin and photoaged skin share important molecular features including connective tissue damage, elevated matrix metalloproteinase levels, and reduced collagen production. In addition, vitamin A treatment reduces matrix metalloproteinase expression and stimulates collagen synthesis in naturally aged, sun-protected skin, as it does in photoaged skin. (+info)
Tretinoin and cutaneous photoaging. Guaranteed adverse effects!
* A cream containing 0.05% tretinoin (Retinova((R)) is approved for treatment of sun-induced skin damage ("photoaging").* Three trials comparing tretinoin with the excipient show that the effects of tretinoin cream are at best limited and slow to occur. Furthermore, they disappear on treatment cessation, necessitating long-term use.* The 0.05% tretinoin cream has poor local tolerability: most subjects develop irritation and fragile skin and require longer intervals between each application. Systemic adverse effects occur in some circumstances.* There are persistent doubts about whether it is safe to use tretinoin during pregnancy. (+info)
Mechanisms and implications of the age-associated decrease in DNA repair capacity.
Skin cancer incidence is clearly linked to UV irradiation and increases exponentially with age. We studied the rate of removal of thymine dimers and (6-4) photoproducts in UV-irradiated human dermal fibroblasts derived from donors of different ages. There was a significant decrease with aging in the repair rates of both thymine dimers and (6-4) photoproducts (P<0.001). In addition, there was an age-associated decrease in the protein levels of ERCC3, PCNA, RPA, XPA, and p53 that participate in nucleotide excision repair. Moreover, the mRNA levels of XPA, ERCC3, and PCNA were significantly reduced with aging, suggesting that these decreases are often regulated at the mRNA level. Furthermore, with age induction of p53 after UV irradiation was significantly reduced. Taken together, our data suggest that the age-associated decrease in the repair of UV-induced DNA damage results at least in part from decreased levels of proteins that participate in the repair process. (+info)
Protection by ultraviolet A and B sunscreens against in situ dipyrimidine photolesions in human epidermis is comparable to protection against sunburn.
Sunscreens prevent sunburn and may also prevent skin cancer by protecting from ultraviolet-induced DNA damage. We assessed the ability of two sunscreens, with different spectral profiles, to inhibit DNA photodamage in human epidermis in situ. One formulation contained the established ultraviolet B filter octyl methoxycinnamate, whereas the other contained terephthalylidene dicamphor sulfonic acid, a new ultraviolet A filter. Both formulations had sun protection factors of 4 when assessed with solar simulating radiation in volunteers of skin type I/II. We tested the hypothesis that sun protection factors would indicate the level of protection against DNA photodamage. Thus, we exposed sunscreen-treated sites to four times the minimal erythema dose of solar simulating radiation, whereas vehicle and control sites were exposed to one minimal erythema dose. We used monoclonal antibodies against thymine dimers and 6-4 photoproducts and image analysis to quantify DNA damage in skin sections. A dose of four times the minimal erythema dose, with either sunscreen, resulted in comparable levels of thymine dimers and 6-4 photoproducts to one minimal erythema dose +/- vehicle, providing evidence that the DNA protection factor is comparable to the sun protection factor. The lack of difference between the sunscreens indicates similar action spectra for erythema and DNA photodamage and that erythema is a clinical surrogate for DNA photodamage that may lead to skin cancer. (+info)
c-Jun-dependent inhibition of cutaneous procollagen transcription following ultraviolet irradiation is reversed by all-trans retinoic acid.
The aged appearance of skin following repeated exposure to solar ultraviolet (UV) irradiation stems largely from damage to cutaneous connective tissue, which is composed primarily of type I and type III collagens. We report here that a single exposure to UV irradiation causes significant loss of procollagen synthesis in human skin. Expression of type I and type III procollagens is substantially reduced within 24 hours after a single UV exposure, even at UV doses that cause only minimal skin reddening. Daily UV exposures over 4 days result in sustained reductions of both type I and type III procollagen protein levels for at least 24 hours after the final UV exposure. UV inhibition of type I procollagen synthesis is mediated in part by c-Jun, which is induced by UV irradiation and interferes with procollagen transcription. Pretreatment of human skin in vivo with all-trans retinoic acid inhibits UV induction of c-Jun and protects skin against loss of procollagen synthesis. We have reported previously that UV irradiation induces matrix-degrading metalloproteinases in human skin and that pretreatment of skin with all-trans retinoic acid inhibits this induction. UV irradiation, therefore, damages human skin connective tissue by simultaneously inhibiting procollagen synthesis and stimulating collagen breakdown. All-trans retinoic acid protects against both of these deleterious effects and may thereby retard premature skin aging. (+info)