Barbara A. Gilchrest

Photoageing : mechanism, prevention and therapy

Photoageing is the superposition of chronic ultraviolet (UV)‐induced damage on intrinsic ageing and accounts for most age‐associated changes in skin appearance. It is triggered by receptor‐initiated signalling, mitochondrial damage, protein oxidation and telomere‐based DNA damage responses. Photodamaged skin displays variable epidermal thickness, dermal elastosis, decreased/fragmented collagen, increased matrix‐degrading metalloproteinases, inflammatory infiltrates and vessel ectasia. The development of cosmetically pleasing sunscreens that protect against both UVA and UVB irradiation as well as products such as tretinoin that antagonize the UV signalling pathways leading to photoageing are major steps forward in preventing and reversing photoageing. Improved understanding of the skin’s innate UV protective mechanisms has also given rise to several novel treatment concepts that promise to revolutionize this field within the coming decade. Such advances should not only allow for the improved appearance of skin in middle age and beyond, but also greatly reduce the accompanying burden of skin cancer.

Treatment of children with port-wine stains using the flashlamp-pulsed tunable dye laser.

Thirty-five children, three months to 14 years of age, with disfiguring port-wine stains were treated with a flashlamp-pulsed tunable dye laser. All had complete clearing of the stains after an average of 6.5 laser treatments to each lesional area; skin over bony prominences required approximately half as many sessions as skin on the cheek. Children less than seven years old required fewer sessions (mean +/- SD, 5.8 +/- 1.1) than older children (7.1 +/- 1.1; P less than 0.05). Treated skin was identical in texture and color to adjacent normal skin in 33 (94.3 percent) of the children, whereas 2 (5.7 percent) had small, isolated, depressed scars in areas accidentally traumatized soon after laser treatment. The only other side effect was transient hyperpigmentation, which occurred in 20 patients (57 percent). These results can be attributed to two distinguishing characteristics of the flashlamp-pulsed tunable dye laser: an emission wavelength of 577 nm, theoretically ideal for selective absorption by the intravascular target oxyhemoglobin, and a pulse duration of 360 microseconds, which closely matches the thermal relaxation time for dermal blood vessels and hence avoids diffuse nonspecific thermal necrosis with subsequent scarring of the treated skin.

Skin aging and photoaging: An overview

As the population ages, common skin disorders of the elderly demand greater attention. Moreover, the many clinical, histologic, and physiologic changes that characterize old skin are increasingly implicated in its vulnerability to environmental injury and certain diseases. Thus it behooves dermatologists to study the basic biologic process of aging in the skin and the separable process of photoaging, which itself is a major clinical problem. To date studies at the cellular level have demonstrated major functional losses, particularly in proliferative capacity between infancy and adulthood, with definite further loss between early and late adulthood and as a result of chronic sun exposure. Continued careful, quantitative assessment of aging and photoaging in human skin both in vivo and in vitro will be critical to a better understanding of these processes and particularly to their successful therapeutic modification.

A review of skin ageing and its medical therapy

Intrinsic (chronological) skin ageing is characterized hy 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 ageinj; process results, at least initially, in a hypcrtrophic repair response, with a thickened epidermis and increased melanogenesis. Even more striking changes occur in the dcrmis: massive elastosis (deposition of abnormal elastic libres). collagen degenerafion. and twisted, dilated microvasculature. ReguUir use of a sunscreen alone appears to allow some repair as well as protection from further photodamage. Topical tretinoin has been shown fo 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 speciiically for the treatment of photodamaged skin, has heen extensively investigated in multifenlre. double‐blind trials and has been shown to produce significant improvement within 4–6 months of daily use, compared witb 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 kcratinocyte ultrastructural damage, more even distribution of melanocytcs 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 compotinds have been reported lo normalize hyperkeratlnization 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 alTect the skin and has demonstrated that many of tbe unwanted changes can be improved by topical therapy.

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.

Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease.

Alzheimers disease is a neurodegenerative disorder characterized by the extracellular deposition in the brain of aggregated beta-amyloid peptide, presumed to play a pathogenic role, and by preferential loss of neurons that express the 75-kD neurotrophin receptor (p75NTR). Using rat cortical neurons and NIH-3T3 cell line engineered to stably express p75NTR, we find that the beta-amyloid peptide specifically binds the p75NTR. Furthermore, 3T3 cells expressing p75NTR, but not wild-type control cells lacking the receptor, undergo apoptosis in the presence of aggregated beta-amyloid. Normal neural crest-derived melanocytes that express physiologic levels of p75NTR undergo apoptosis in the presence of aggregated beta-amyloid, but not in the presence of control peptide synthesized in reverse. These data imply that neuronal death in Alzheimers disease is mediated, at least in part, by the interaction of beta-amyloid with p75NTR, and suggest new targets for therapeutic intervention.

Oral methoxsalen photochemotherapy of mycosis fungoides

The cutaneous manifestations of mycosis fungoides have been successfully treated in nine patients for 16 to 28 months with oral methoxsalen and subsequent irradiation with longwave ultraviolet light. The efficacy of this therapy was confirmed in one patient, who showed complete clearing of generalized plaques after 1 month (12 treatments) except for a shielded control area which worsened during this period. Methoxsalen photochemotherapy may prove a valuable addition to therapies currently available for mycosis fungoides and may obviate some of the problems associated with conventional management of this disorder.

The human sunburn reaction: Histologic and biochemical studies

The ultraviolet-induced erythema reaction was investigated histologically and biochemically in four subjects, utilizing suction blister aspirates, analyzed for histamine and prostaglandin E2 (PGE2), and Epon-embedded 1-mu skin biopsy sections from control skin and from irradiated skin at intervals for 72 hours after exposure to a Hanovia lamp. Major histologic alterations in the epidermis included dyskeratotic and vacuolated keratinocytes (sunburn cells), and disappearance of Langerhans cells. In the dermis the major changes were vascular, involving both the superficial and deep venular plexuses. Endothelial cell enlargement was first apparent within 30 minutes of irradiation, peaked at 24 hours, and persisted throughout the 72-hour study period. Mast cell degranulation and associated perivenular edema were first apparent at 1 hour and striking at the onset of erythema, 3 to 4 hours postirradiation; edema was absent and mast cells were again normal in number and granule content at 24 hours. Histamine levels rose approximately fourfold above control values immediately after the onset of erythema and returned to baseline within 24 hours. PGE2 levels were statistically elevated even before the onset of erythema and reached approximately 150% of the control value at 24 hours. These data provide the first evidence that histamine may mediate the early phase of the human sunburn reaction and increase our understanding of its complex histologic and biochemical sequelae.

Photoaging/photodamage and photoprotection

Exposure to sunlight can produce both acute and long-term effects. Acute changes include erythema, photosensitivity, and immunologic alterations. Long-term consequences include carcinogenesis and photoaging. All effects can be minimized by photoprotection. This article reviews the adverse effects of sun exposure and strategies to reduce photodamage.

SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit

ABSTRACT Hair graying, an age‐associated process of unknown etiology, is characterized by a reduced number and activity of hair follicle (HF) melanocytes. Stem cell factor (SCF) and its receptor c‐kit are impor¬tant for melanocyte survival during development, and mutations in these genes result in unpigmented hairs. Here we show that during cyclic HF regeneration in C57BL/6 mice, proliferating, differentiating, and mel¬anin‐producing melanocytes express c‐kit, whereas pre¬sumptive melanocyte precursors do not. SCF overex¬pression in HF epithelium significantly increases the number and proliferative activity of melanocytes. Dur¬ing the induced hair cycle in C57BL/6 mice, adminis¬tration of anti‐c‐kit antibody dose‐dependently de¬creases hair pigmentation and leads to partially depigmented (gray) or fully depigmented (white) hairs, associated with significant decreases in melanocyte proliferation and differentiation, as determined by immunostaining and confocal microscopy. However, in the next hair cycle, the previously treated animals grow fully pigmented hairs with the normal number and distribution of melanocytes. This suggests that melanocyte stem cells are not dependent on SCF/c‐kit and when appropriately stimulated can generate melanogenically active melanocytes. Therefore, the blockade of c‐kit signaling offers a fully reversible model for hair depigmentation, which might be used for the studies of hair pigmentation disorders.—Botchkareva, N. V., Khlgatian, M., Longley, B. J., Botchkarev, V. A., and Gilchrest, B. A. SCF/c‐kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J. 15, 645‐658 (2001)