Topical tretinoin: photodamage treatment overview and developmental toxicology studies. Introduction.
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Administration, Topical↗
Biomedical subjects
B A Gilchrest
Publications and source records attributed to B A Gilchrest.
Treatment of photodamage with topical tretinoin: an overview.
Topical administration of tretinoin has proved to be effective in treating clinical signs of photodamaged skin. In large-scale, double-blind, placebo-controlled, 6-month trials, 0.05% tretinoin emollient cream (Renova, Retinova) reduced fine wrinkles and skin roughness, and it produced histologic changes such as epidermal thickening, increased granular layer thickness, stratum comeum compaction, and decreased melanin content. Smaller changes were also observed at lower tretinoin concentrations. Continued for another 6 months, 0.05% tretinoin emollient cream produced some additional clinical improvement but the histologic changes observed in the epidermis (with the exception of melanin content) regressed toward baseline, raising questions as to what was responsible for the clinical improvement. After 12 months of treatment, there were additional signs of tissue normalization including deposition of new collagen in the papillary dermis and ultrastructural evidence of dermal reconstruction with improvement in the dermoepidermal junction and correction of keratinocyte degeneration, changes that presumably relate directly to tretinoin's mechanism of action. There was no suggestion of cytologic atypia in these studies or in biopsy specimens obtained after up to 4 years of continued use. Mild to moderate dermatitis was the only common adverse reaction to tretinoin use. Percutaneous tretinoin absorption is low, raising plasma levels by amounts that are negligible compared with the normally low endogenous tretinoin levels. No teratogenic effects have been observed in retrospective studies of topical tretinoin application during the first trimester of pregnancy. Thus, topical tretinoin is safe and effective in the treatment of photodamage.
Administration, Topical↗
Aging processes, DNA damage, and repair.
The second triennial FASEB Summer Research Conference on "Clonal Senescence and Differentiation" (August 17-22, 1996) focused on the interrelationships between aging processes and DNA damage and repair. The attendees represented a cross section of senior and junior investigators working in fields ranging from classic cellular gerontology to yeast and nematode models of aging to basic mechanisms of DNA damage and repair. The meeting opened with a keynote address by Dr. Bruce Ames that emphasized the documented relationships between oxidative damage, cancer, and aging. This was followed by eight platform sessions, one poster discussion, one featured presentation, and an after-dinner address. The following sections highlight the key points discussed.
Aging↗
Human melanocytes as a model system for studies of Alzheimer disease.
The aging process leads to increased vulnerability to injury and disease, resulting in a decline in 1 or more organ systems that is incompatible with life. One of the most devastating age-associated neurodegenerative disorders, Alzheimer disease, is characterized by neuronal loss and the extracellular deposition in the brain of beta-amyloid peptide, which is presumed to be causally related. Using cultured neural crest-derived cutaneous melanocytes, we find that in the presence of beta-amyloid, melanocytes, like neurons, undergo programmed cell death (apoptosis). Nerve growth factor, which has been reported to attenuate the loss of cholinergic neurons in Alzheimer disease, protects melanocytes from apoptosis induced by beta-amyloid. Moreover, beta-amyloid is a ligand for the 75-kD transmembrane neurotrophin receptor that belongs to the family of apoptotic receptors that generates a cell-death signal on activation. Our data suggest that neuronal death in Alzheimer disease is mediated by the interaction of beta-amyloid with the 75-kD neurotrophin receptor. Human melanocytes provide a valuable in vitro model for studies of Alzheimer disease and for development of potential therapies.
Aging↗
Innervation of melanocytes in human skin.
Communication between the nervous system and epidermal melanocytes has been suspected on the basis of their common embryologic origin and apparent parallel involvement in several disease processes, but never proven. In this study, confocal microscopic analysis of human skin sections stained with antibodies specific for melanocytes and nerve fibers showed intraepidermal nerve endings in contact with melanocytes. This intimate contact was confirmed by electron microscopy, which further demonstrated thickening of apposing plasma membranes between melanocytes and nerve fibers, similar to synaptic contacts seen in nervous tissue. Since many intraepidermal nerve fibers are afferent nerves that act in a "neurosecretory" fashion through their terminals, cultured human melanocytes were stimulated with calcitonin gene-related peptide (CGRP), substance P, or vasoactive intestinal peptide, neuropeptides known to be present in cutaneous nerves, to examine their possible functions in the epidermal melanin unit. CGRP increased DNA synthesis rate of melanocytes in a concentration- and time-dependent manner. Cell yields after 5 d were increased 25% compared with controls maintained in an otherwise optimized medium. Furthermore, stimulation by CGRP induced rapid and dose-dependent accumulation of intracellular cAMP, suggesting that the mitogenic effect is mediated by the cAMP pathway. These studies confirm and expand a single earlier report in an animal model of physical contact between melanocytes and cutaneous nerves and for the first time strongly suggest that the nervous system may exert a tonic effect on melanocytes in normal or diseased human skin.
Calcitonin Gene-Related Peptide↗
Aging affects epidermal growth factor receptor phosphorylation and traffic kinetics.
With increasing donor age, cultured human fibroblasts express fewer epidermal growth factor receptors and display decreased mitogenic responsiveness to epidermal growth factor. To determine age-associated differences in epidermal growth factor receptor phosphorylation and traffic kinetics, we studied in fibroblasts derived from donors of different ages autophosphorylation of the receptor after ligand binding and trafficking of the receptor-ligand complexes. We now report an age-associated delay in the rate of receptor phosphorylation after epidermal growth factor stimulation. Furthermore, receptor/ligand trafficking is affected by aging. There is an age-associated decrease and delay in the number of occupied receptors that are transported intracellularly and in their rate of clearance from the plasma membrane. Our data show that aging affects receptor/ligand activation and processing and suggest that the decreased cellular mitogenic response with aging may be, at least in part, the result of decrements in receptor activation and processing.
Biological Transport↗
Alpha-melanocyte stimulating hormone-induced pigmentation is blocked by depletion of protein kinase C.
We have explored the role of protein kinase C (PKC) in pigmentation induced by alpha-melanocyte stimulating hormone (alpha-MSH). Using the well-studied S91 Cloudman mouse melanoma model system in which 10(-7) M alpha-MSH is known to produce a time-dependent increase in pigmentation, we found an increase in the activity of tyrosinase, the key enzyme in pigmentation, between Days 2 and 6 accompanied by an increase in mRNA and protein levels of tyrosinase, as well as an increase in the level of specifically the beta isoform of PKC. When S91 cells were treated with phorbol dibutyrate, 95% of PKC activity was lost within 48 h and the alpha-MSH-induced melanogenesis was completely blocked, as was the induction of tyrosinase mRNA and protein. Serially passaged S91 cells no longer capable of responding to alpha-MSH had an undetectable level of PKC-beta, although the tyrosinase protein level was identical to that of alpha-MSH-responsive cells. Furthermore, in these S91 cells alpha-MSH also did not increase the level of tyrosinase mRNA. Thus, induction of murine melanogenesis by alpha-MSH involves up-regulation of tyrosinase mRNA and protein mediated in part by the PKC-dependent pathway, associated with an up-regulation of the beta isoform previously demonstrated to specifically activate tyrosinase in human melanocytes.
Alkaloids↗
Nerve growth factor rescues pigment cells from ultraviolet-induced apoptosis by upregulating BCL-2 levels.
Apoptosis plays an important role in eliminating dysfunctional damaged cells. For skin, the best characterized injurious environmental agent is ultraviolet (UV) irradiation. Most of the damaging UV irradiation is absorbed in the epidermis and leads to apoptosis of keratinocytes. However, epidermal melanocytes appear to be protected from UV-induced apoptosis. We now report that in pure cultures melanocytic cells undergo characteristic apoptosis after physiologic UV exposures. However, nerve growth factor (NGF) supplementation protects them from this programmed cell death. Furthermore, we show that NGF protects melanocytic cells from UV-induced apoptosis by upregulating BCL-2 protein in these cells and that prior downregulation of BCL-2 abrogates the NGF protective effect on melanocytes. Our data suggest that NGF, known to be constitutively produced by epidermal keratinocytes and induced in these cells after UV irradiation, may preserve the population of cutaneous melanocytes that would otherwise be depleted by casual sun exposure.
Apoptosis↗
DNA damage enhances melanogenesis.
Although the ability of UV irradiation to induce pigmentation in vivo and in vitro is well documented, the intracellular signals that trigger this response are poorly understood. We have recently shown that increasing DNA repair after irradiation enhances UV-induced melanization. Moreover, addition of small DNA fragments, particularly thymine dinucleotides (pTpT), selected to mimic sequences excised during the repair of UV-induced DNA photoproducts, to unirradiated pigment cells in vitro or to guinea pig skin in vivo induces a pigment response indistinguishable from UV-induced tanning. Here we present further evidence that DNA damage and/or the repair of this damage increases melanization. (i) Treatment with the restriction enzyme Pvu II or the DNA-damaging chemical agents methyl methanesulfonate (MMS) or 4-nitroquinoline 1-oxide (4-NQO) produces a 4- to 10-fold increase in melanin content in Cloudman S91 murine melanoma cells and an up to 70% increase in normal human melanocytes, (ii) UV irradiation, MMS, and pTpT all upregulate the mRNA level for tyrosinase, the rate-limiting enzyme in melanin biosynthesis. (iii) Treatment with pTpT or MMS increases the response of S91 cells to melanocyte-stimulating hormone (MSH) and increases the binding of MSH to its cell surface receptor, as has been reported for UV irradiation. Together, these data suggest that UV-induced DNA damage and/or the repair of this damage is an important signal in the pigmentation response to UV irradiation. Because Pvu II acts exclusively on DNA and because MMS and 4-NQO, at the concentrations used, primarily interact with DNA, such a stimulus alone appears sufficient to induce melanogenesis. Of possible practical importance, the dinucleotide pTpT mimics most, if not all, of the effects of UV irradiation on pigmentation, tyrosinase mRNA regulation, and response to MSH without the requirement for antecedent DNA damage.
4-Nitroquinoline-1-oxide↗
Photobiology. Wrinkles waiting for GoDoT.
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Aging↗
Cosmeceuticals. A proposal for rational definition, evaluation, and regulation.
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Cosmetics↗
Regulation of keratinocyte growth factor gene expression in human skin fibroblasts.
Human keratinocyte growth factor (KGF) is a recently identified mitogen for epithelial cells produced by normal stromal fibroblasts. KGF has been shown to stimulate keratinocyte migration and promote re-epithelialization of skin suggesting a critical role for KGF in wound healing. To understand how KGF might be regulated during wound healing, we examined the ability of the pro-inflammatory cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta) interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) transforming growth factor-beta 1 (TGF-beta 1) and interferon-gamma (IFN-gamma) to modulate KGF gene expression in cultured human fibroblasts, using northern blot analysis. Exposure to IL-1 alpha (20 units/ml) or IL-1 beta (100 units/ml) for 24 h increased KGF mRNA expression by 352% and 504%, respectively, with early induction seen at 2 h and maximal induction seen at 8 h. TNF-alpha (30 ng/ml) increased KGF mRNA expression by 535% at 24 h, with induction first seen at 8 h. The maximal induction of KGF mRNA was observed when IL-1 alpha, IL-1 beta and TNF-alpha were used at 100 units/ml, and 3 ng/ml, respectively, although concentrations 100-500-fold lower (IL-1 alpha, 0.02 units/ml; IL-beta, 0.02 units/ml; and TNF-alpha, 0.03 ng/ml) were nearly as stimulatory, increasing KGF mRNA expression by 175%, 254% and 322%, respectively. IL-6 (200 units/ml), TGF-beta 1 (5 ng/ml) and IFN-gamma (200 units/ml) did not change the level of KGF mRNA at 24 h in human fibroblasts under the same conditions. The protein synthesis inhibitor cycloheximide abrogated the effects of IL-1 alpha, IL-1 beta and TNF-alpha on KGF gene induction, indicating that new protein synthesis is required in the process. Dexamethasone (10(-7) M), known to inhibit inflammatory reactions and retard wound healing, also inhibited the induction of KGF mRNA expression by IL-1 alpha, IL-1 beta and TNF-alpha. Individual variation in KGF mRNA expression was see when fibroblasts from different aged donors were analysed, but no consistent age-associated change was observed. These results suggest that IL-1 alpha, IL-1 beta and TNF-alpha up-regulate KGF gene expression in fibroblasts and might be responsible for its induction following skin wounding or other injury.
Adult↗
Histologic evaluation of the long term effects of tretinoin on photodamaged skin.
Sustained improvement with prolonged topical tretinoin for photodamaged skin has been well documented for up to 22 months of continuous treatment. We now report long-term (4 years) histologic effects of topical tretinoin in photodamaged skin of 27 patients, the longest study to date. The observed decreases in dermal elastin content and perivascular inflammation and increase in epidermal mucin in facial biopsies obtained after up to 4 years of treatment may be partly responsible for the continued clinical improvement. Furthermore, the study shows that there are no untoward effects on keratinocytes or melanocytes during long-term use of topical tretinoin.
Double-Blind Method↗
A review of skin ageing and its medical therapy.
Intrinsic (chronological) skin ageing is characterized by atrophy of the skin with loss of elasticity and slowed metabolic activity. The superposition of environmental damage, particularly exposure to ultraviolet radiation (photodamage), on the intrinsic ageing process results, at least initially, in a hypertrophic repair response, with a thickened epidermis and increased melanogenesis. Even more striking changes occur in the dermis: massive elastosis (deposition of abnormal elastic fibres), collagen degeneration, and twisted, dilated microvasculature. Regular use of a sunscreen alone appears to allow some repair as well as protection from further photodamage. Topical tretinoin has been shown to partially reverse the clinical and histological changes induced by the combination of sunlight exposure and chronological ageing. A formulation of tretinoin in an emollient cream (Retinova, Renova), developed specifically for the treatment of photodamaged skin, has been extensively investigated in multicentre, double-blind trials and has been shown to produce significant improvement within 4-6 months of daily use, compared with vehicle alone, as part of a regimen including sun protection and moisturizer use. Histological changes in the epidermis and dermis noted after 12 months suggest tretinoin repairs photodamage by reconstitution of the rete pegs, repair of keratinocyte ultrastructural damage, more even distribution of melanocytes and melanin pigment, deposition of new papillary dermal collagen, and improvements in vasculature. Alpha-hydroxy acids (AHAs) have also been widely used for therapy of photodamaged skin, and these compounds have been reported to normalize hyperkeratinization and increase viable epidermal thickness and dermal glycosaminoglycans content. The single randomized controlled study now available appears to substantiate AHA efficacy and safety. In summary, recent work has substantially elucidated the ageing processes that affect the skin and has demonstrated that many of the unwanted changes can be improved by topical therapy.
Humans↗
Proopiomelanocortin, its derived peptides, and the skin.
Proopiomelanocortin (POMC) is a protein synthesized predominately in the pituitary gland but also in a variety of other tissues, including the skin. Through enzyme-mediated cleavage that varies among cell types, POMC can give rise to at least eight distinct peptides whose biologic roles are incompletely delineated. Although blood-borne pituitary-derived bioactivity for the skin was first recognized 80 years ago and the responsible neuropeptides isolated 20-40 years ago, our understanding of POMC-derived peptides in skin is still rapidly evolving. In particular, recent work in cultured human and murine skin-derived cells has demonstrated POMC gene expression as well as modulation of POMC and many of its derived peptides in response to physiologic signals including ultraviolet irradiation and cytokines. Immunoreactivity for these peptides has also been detected in normal skin and hair follicles, strongly suggesting cutaneous synthesis in vivo. Candidate autocrine or paracrine functions include enhanced melanogenesis, immunomodulation, and effects on cell cycle regulation and differentiated function in both the epidermis and its appendages. This article reviews recent data concerning POMC gene expression and regulation, protein processing, signal transduction, and biologic functions relevant to cutaneous biology.
Gene Expression↗
Proopiomelanocortin gene product regulation in keratinocytes.
Proopiomelanocortin (POMC) is the precursor for adrenocorticotropic hormone, melanocyte-stimulating hormones, beta-lipotropic hormone (beta LPH), and beta endorphin. These peptides can function as neurotransmitters, modulate immune responses, and affect melanogenesis. We investigated POMC expression and protein processing in normal human keratinocytes. On Northern blot analysis, the baseline expression of the 1.2-kb POMC transcript was upregulated by ultraviolet radiation (UVR) or by stimulation with interleukin-1 alpha (IL-1 alpha) or phorbol 12-tetradecanoate 13-acetate (TPA). On Western blot analysis, POMC, beta LPH, and beta-endorphin were detected in cell extracts under baseline conditions. beta LPH level increased substantially after UVR, IL-1 alpha, or TPA. Within 36 h after TPA stimulation, beta-endorphin became undetectable in cell extracts, coinciding with an increase of beta-endorphin-immunoreactive protein in the culture medium. Our data establish that keratinocytes synthesize POMC protein as well as its derivatives beta LPH and beta-endorphin, and that this process is modulated by TPA, IL-1A, and UVR. beta LPH and beta-endorphin of keratinocyte origin may thus be involved in melanogenesis and/or immunomodulation in the skin after sun exposure, and their release into the circulation may also have systemic effects.
Cells, Cultured↗
Enzyme therapy of xeroderma pigmentosum: safety and efficacy testing of T4N5 liposome lotion containing a prokaryotic DNA repair enzyme.
Xeroderma pigmentosum (XP) is a rare genetic disease in which patients are defective in DNA repair and are extremely sensitive to solar UV radiation exposure. A new treatment approach was tested in these patients, in which a prokaryotic DNA repair enzyme specific for UV-induced DNA damage was delivered into the skin by means of topically applied liposomes to supplement the deficient activity. Acute and chronic safety testing in both mice and humans showed neither adverse reactions nor significant changes in serum chemistry or in skin histology. The skin of XP patients treated with the DNA repair liposomes had fewer cyclobutylpyrimidine dimers in DNA and showed less erythema than did control sites. The results encourage further clinical testing of this new enzyme therapy approach.
Adolescent↗
Mechanisms of ultraviolet light-induced pigmentation.
Work in the past 8 years, particularly in the past 1-2 years, has greatly expanded our understanding of the mechanisms by which ultraviolet irradiation stimulates melanogenesis in the skin. A direct effect of UV photons on DNA results in up-regulation of the gene for tyrosinase, the rate-limiting enzyme in melanin synthesis, as well as an increase in cell surface expression of receptors for at least one of the several known keratinocyte-derived melanogenic factors, MSH. Direct effects of UV on melanocyte membranes, releasing DAG and arachidonic acid, may also play a role in the tanning response. Diacylglycerol may activate PKC-beta, which in turn phosphorylates and activates tyrosinase protein; the pathways by which products of other inflammatory mediator cascades may act on melanogenesis are unknown. The tanning response also relies heavily on UV-stimulated increased production and release of numerous keratinocyte-derived factors including bFGF, NGF, endothelin-1 and the POMC-derived peptides MSH, ACTH, beta-LPH and beta-endorphin. These factors variably induce melanocyte mitosis, increase melanogenesis, enhance dendricity and prevent apoptotic cell death following the UV injury. Thus, events within the epidermal melanin unit conspire to maintain or increase melanocyte number, increase melanin pigment throughout the epidermis. Overall, ultraviolet-induced melanogenesis may be one part of a eukaryotic SOS response to damaging ultraviolet irradiation that has evolved over time to provide a protective tan in skin at risk of further injury from sun exposure. These recent insights into the mechanisms underlying ultraviolet-induced melanogenesis offer the opportunity for novel therapeutic approaches to minimizing acute and chronic photodamage in human skin.
Cell Communication↗