Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light

Fisher, Gary J.; Wang, Zeng Quan; Datta, Subhash C.; Varani, James; Kang, Sewon; Voorhees, John J.

doi:10.1056/nejm199711133372003

Cited by 1,305 publications

(1,164 citation statements)

References 36 publications

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“…This is in contrast to findings from studies with acute UV-irradiated skin, where increased collagenase was observed relative to nonirradiated controls. 7,8 This is also in contrast to findings in natural aging, where a higher level of collagenase was observed in sun-protected skin from Ͼ80-year-old individuals than in sun-protected skin of younger (18-to 29-year-old) individuals. 42 Because dermal fibroblasts do not seem to be intrinsically damaged in severely photoaged skin, it follows that inhibitory influences within the in vivo environment of severely photodamaged skin may act in some way to prevent cells that are inherently capable of elaborating collagen from doing so.…”

Section: Discussioncontrasting

confidence: 54%

“…By focusing on collagenous components in the present study, we do not mean to rule out possible contributions of other components of the extracellular matrix. Regardless of the molecular mechanisms underlying reduced collagen synthesis in photodamaged skin, the beneficial effects of agents such as all-trans retinoic acid may derive not only from direct action on fibroblasts to stimulate collagen synthesis 9,10 and decrease collagenase expression, 7,8 but also from indirectly promoting (through the newly synthesized collagen) additional matrix-regenerative signals not present in untreated photodamaged skin.…”

Section: Discussionmentioning

confidence: 99%

“…Exposure of skin to UV irradiation transiently up-regulates production of MMPs that are capable of degrading skin collagen. 7,8 Repeated MMP induction throughout years or decades could give rise to the damage seen in the matrix of chronically sun-exposed skin. Although proteolytic attack on structural collagen is clearly part of the overall process, failure to replace damaged collagen with newly synthesized collagen also contributes to the progressive degenerative changes that occur in the connective tissue of sunexposed skin throughout time.…”

Section: Discussionmentioning

confidence: 99%

“…1-6 Acute exposure of human skin in vivo to ultraviolet (UV) irradiation up-regulates synthesis of several matrix metalloproteinases (MMPs) including MMP-1 (interstitial collagenase), MMP-3 (stromelysin-1), and MMP-9 (92-kd gelatinase B) that degrade skin collagen. 7,8 Repeated induction of these matrix-degrading enzymes, after exposure to solar irradiation, throughout a period of years or …”

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confidence: 99%

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Inhibition of Type I Procollagen Synthesis by Damaged Collagen in Photoaged Skin and by Collagenase-Degraded Collagen in Vitro

Varani

Spearman

Perone

et al. 2001

The American Journal of Pathology

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290

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Type I and type III procollagen are reduced in photodamaged human skin. This reduction could result from increased degradation by metalloproteinases and/or from reduced procollagen synthesis. In the present study, we investigated type I procollagen production in photodamaged and sun-protected human skin. Skin samples from severely sun-damaged forearm skin and matched sun-protected hip skin from the same individuals were assessed for type I procollagen gene expression by in situ hybridization and for type I procollagen protein by immunostaining. Both mRNA and protein were reduced (ϳ65 and 57%, respectively) in photodamaged forearm skin compared to sun-protected hip skin. We next investigated whether reduced type I procollagen production was because of inherently reduced capacity of skin fibroblasts in severely photodamaged forearm skin to synthesize procollagen, or whether contextual influences within photodamaged skin act to down-regulate type I procollagen synthesis. For these studies, fibroblasts from photodamaged skin and matched sunprotected skin were established in culture. Equivalent numbers of fibroblasts were isolated from the two skin sites. Fibroblasts from the two sites had similar growth capacities and produced virtually identical amounts of type I procollagen protein. These findings indicate that the lack of type I procollagen synthesis in sun-damaged skin is not because of irreversible damage to fibroblast collagen-synthetic capacity. It follows, therefore, that factors within the severely photodamaged skin may act in some manner to inhibit procollagen production by cells that are inherently capable of doing so. Interactions between fibroblasts and the collagenous extracellular matrix regulate type I procollagen synthesis. In sun-protected skin, collagen fibrils exist as a highly organized matrix. Fibroblasts are found within the matrix, in close apposition with collagen fibers. In photodamaged skin, collagen fibrils are shortened, thinned, and disorganized. The level of partially degraded collagen is ϳ3.6-fold greater in photodamaged skin than in sun-protected skin, and some fibroblasts are surrounded by debris. To model this situation, skin fibroblasts were cultured in vitro on intact collagen or on collagen that had been partially degraded by exposure to collagenolytic enzymes. Collagen that had been partially degraded by exposure to collagenolytic enzymes from either bacteria or human skin underwent contraction in the presence of dermal fibroblasts, whereas intact collagen did not. Fibroblasts cultured on collagen that had been exposed to either source of collagenolytic enzyme demonstrated reduced proliferative capacity (22 and 17% reduction on collagen degraded by bacterial collagenase or human skin collagenase, respectively) and synthesized less type I procollagen (36 and 88% reduction, respectively, on a per cell basis). Taken together, these findings indicate that 1) fibroblasts from photoaged and sun-protected skin are similar in their capacities for growth and type I procollagen productio...

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Type I Procollagen Synthesis by Damaged Collagen in Photoaged Skin and by Collagenase-Degraded Collagen in Vitro

Varani

Spearman

Perone

et al. 2001

The American Journal of Pathology

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290

208

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“…Ultraviolet irradiation (UV) of human skin is known to be involved in the pathogenesis of several disorders characterized by inflammation, hyperpigmentation and hyperproliferation, and possibly leading to tumorigenesis (Fisher et al, 1997;Glenn McGregor, 1999;Wikonkal and Brash, 1999). Exposure to UV radiation causes a complex cellular response, which includes the regulation of gene expression, DNA damage, lipid peroxidation and induction of apoptosis (Schwarz et al, 1995;Rosette and Karin, 1996;Sheikh et al, 1998;Glenn McGregor, 1999;Wikonkal and Brash, 1999).…”

Section: Introductionmentioning

confidence: 99%

UVB-induced activation and internalization of keratinocyte growth factor receptor

et al. 2003

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Ultraviolet irradiation of mammalian cells induces several events that include activation of growth factor receptors and triggering of signal transduction pathway. Most of the UV responses are mediated by the production of reactive oxygen species (ROS) and can be blocked by antioxidants. In this study, we analysed the effect of UVB irradiation at physiologic doses and that of the prooxidant agent cumene hydroperoxide (CUH) on the activation of the receptor for keratinocyte growth factor (KGF), a key mediator of epithelial growth and differentiation. Exposure to both UVB (30-150 mJ/cm 2 ) and CUH (200 lm of NIH3T3 KGFR (KGF receptors) transfectants caused a rapid tyrosine phosphorylation and activation of KGFR similar to that induced by KGF, and internalization of the activated receptor. The KGFR expression appeared unmodified by the treatments. Ultrastructural observations of both UVB-and CUHtreated cells showed a normal morphology of the plasma membranes and intracellular organelles. The antioxidant N-acetylcysteine inhibited UVB-induced receptor phosphorylation. The generation of an intracellular oxidative stress was detected as a decrease of catalase activity and of vitamin E, and reduced glutathione levels, whereas superoxide dismutase activity was not significantly modified. A peroxidation of polyunsaturated fatty acids of cell membranes was observed after both treatments, associated with the intracellular oxidative stress. Similar biochemical events were observed on NIH3T3 untransfected control cells, suggesting that KGFR activation follows intracellular generation of ROS and is not associated with a scavenging effect. Taken together our results demonstrate that exposure to UVB and to oxidant stimuli induces a rapid intracellular production of ROS, which in turn are capable of triggering KGFR activation and internalization, similar to those induced by KGF.

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Cryogen Spray Cooling in Combination With Nonablative Laser Treatment of Facial Rhytides

Kelly¹,

Nelson²,

Lask³

et al. 1999

Arch Dermatol

210

135

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Background: Cryogen spray cooling can be used to provide epidermal protection while still achieving spatially selective photocoagulation in the upper dermis. The objective of this study is to determine the efficacy and safety of cryogen spray cooling in combination with a nonablative Nd:YAG (= 1320 nm) laser treatment of facial rhytides in human volunteers. Observations: Thirty-five adults with bilateral periorbital rhytides were treated with cryogen spray cooling in combination with 3 nonablative laser treatments performed sequentially at intervals of 2 weeks. Small but statistically significant improvements were noted in the mild, moderate, and severe rhytid groups 12 weeks after the final laser treatment. A final assessment performed 24 weeks after the last treatment showed statistically sig

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Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light

Abstract: Multiple exposures to ultraviolet irradiation lead to sustained elevations of matrix metalloproteinases that degrade skin collagen and may contribute to photoaging. Treatment with topical tretinoin inhibits irradiation-induced matrix metalloproteinases but not their endogenous inhibitor.

Cited by 1,305 publications

References 36 publications

Inhibition of Type I Procollagen Synthesis by Damaged Collagen in Photoaged Skin and by Collagenase-Degraded Collagen in Vitro

Inhibition of Type I Procollagen Synthesis by Damaged Collagen in Photoaged Skin and by Collagenase-Degraded Collagen in Vitro

UVB-induced activation and internalization of keratinocyte growth factor receptor

Cryogen Spray Cooling in Combination With Nonablative Laser Treatment of Facial Rhytides

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