Christian Meewes

Photoaging of the skin from phenotype to mechanisms

The skin is increasingly exposed to ambient UV-irradiation thus increasing its risk for photooxidative damage with longterm detrimental effects like photoaging, which is characterized by wrinkles, loss of skin tone, and resilience. Photoaged skin displays prominent alterations in the cellular component and the extracellular matrix of the connective tissue with an accumulation of disorganized elastin and its microfibrillar component fibrillin in the deep dermis and a severe loss of interstitial collagens, the major structural proteins of the dermal connective tissue. The unifying pathogenic agents for these changes are UV-generated reactive oxygen species (ROS) that deplete and damage non-enzymatic and enzymatic antioxidant defense systems of the skin. As well as causing permanent genetic changes, ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence, and connective tissue degradation. This review focuses on the role of UV-induced ROS in the photodamage of the skin resulting in biochemical and clinical characteristics of photoaging. In addition, the relationship of photoaging to intrinsic aging of the skin will be discussed. A decrease in the overall ROS load by efficient sunscreens or other protective agents may represent promising strategies to prevent or at least minimize ROS induced photoaging.

Adaptive antioxidant response protects dermal fibroblasts from UVA-induced phototoxicity

In response to the attack of reactive oxygen species (ROS) produced upon UV irradiation, the skin has developed a complex antioxidant defense system. Here we report that, in addition to the previously published induction of manganese superoxide dismutase (MnSOD) activity, single and, to a higher extent, repetitive low-dose UVA irradiation also leads to a substantial upregulation of glutathione peroxidase (GPx) activity. This concomitant adaptive response of two antioxidant enzymes acting in the same detoxification pathway coincided with the protection from high-UVA-dose-induced cytotoxicity conferred by low-dose UVA preirradiation. Whereas an interval of 24 h did not, an interval of 12 h did lead to the induction of MnSOD activity and, under selenium-supplemented conditions, of GPx activity as well, conferring definite cellular protection from UVA-induced phototoxicity. Moreover, under selenium-deficient conditions, which abrogate the UVA-mediated induction of GPx activity, adaptive protection against the cytotoxic effects of high UVA doses was significantly lower compared with selenium supplementation. Isolated 4.6-fold overexpression of MnSOD activity in stably transfected fibroblasts led to specific resistance from UVA-mediated phototoxicity under selenium-deficient conditions. Collectively, these data indicate that the concomitant induction of MnSOD and GPx activity is related to the optimal adaptive protection from photooxidative damage. This adaptive antioxidant protection clearly depends on the irradiation interval and a sufficient selenium concentration, findings that may have important implications for the improvement of photoprotective and phototherapeutic strategies in medicine.

The first peak of the UVB irradiation‐dependent biphasic induction of vascular endothelial growth factor (VEGF) is due to phosphorylation of the epidermal growth factor receptor and independent of autocrine transforming growth factor α

Ultraviolet B (UVB) irradiation, the major damaging component of sunlight, has earlier been reported to enhance cutaneous angiogenesis in chronically sun‐exposed skin. We herein provide first evidence for a biphasic induction of the vascular endothelial growth factor (VEGF) following UVB irradiation of the human epidermal cell line HaCaT. The first VEGF peak occurred on mRNA level at 1 h and on protein level at 4 h postirradiation and is fully mediated by the UVB‐dependent phosphorylation of the epidermal growth factor receptor, which subsequent to its phosphorylation also initiates at least in part the synthesis of transforming growth factor α that confers as shown previously the second late VEGF peak at 8 h on mRNA and at 24 h on protein level.

Chapter 6 - The negative effects of solar and artificial irradiation: photoaging of the skin, its clinical appearance and underlying mechanisms

Abstract The skin is increasingly exposed to ambient UV-irradiation thus increasing its risk for photooxidative damage with long-term detrimental effects like photoaging, which is characterized by wrinkles, loss of skin tone and resilience. Photoaged skin displays prominent alterations in the cellular component and extracellular matrix of the connective tissue with an accumulation of disorganized elastin and its microfibrillar component fibrillin in the deep dermis and a severe loss of interstitial collagens, the major structural proteins of the dermal connective tissue. The unifying pathogenic agents for these changes are UV-generated reactive oxygen species (ROS) which deplete and damage non-enzymatic and enzymatic antioxidant defense systems of the skin. As well as causing permanent genetic changes, ROS activate cytoplasmic signal transduction pathways in resident fibroblasts that are related to growth, differentiation, senescence and connective tissue degradation. This review focuses on the role of UV-induced ROS in the photodamage of the skin resulting in clinical and biochemical characteristics of photoaging. In addition, the relationship of photoaging to intrinsic aging of the skin will be briefly discussed. A decrease in the overall ROS load by efficient sunscreens or other protective agents may represent promising strategies to prevent or at least minimize ROS-induced photoaging.

Adaptive antioxidant defence in human dermal fibroblasts

Sir, Epidermal grafting with suction blisters is used in treatment of stable vitiligo. Previous reports have shown various complications including postinflammatory hyperpigmentation, peripheral hypopigmentation and hypertrophic scarring. However, the risk of infection has not been reported to date. We report an unusual case of verruca vulgaris that appeared after epidermal grafting. It seems likely that virus particles might have been transferred from the operator, who had verruca vulgaris on his hand, to the patient during the surgical procedure. A 12-year-old girl with localized stable vitiligo was treated by epidermal grafting. Blisters on the recipient site formed within 24 h after three freeze±thaw cycles with liquid nitrogen. Blisters on the donor site were made by suction on the inner portion of the thigh. After approximately 3 h of suction at 200 mmHg, large unilocular bullae appeared. After removal of the blisters at the recipient site, the epidermal sheets were grafted to the denuded recipient site and held in place. Two weeks after grafting, once weekly systemic psoralen-ultraviolet A treatment was started. Almost complete repigmentation was observed 3 months after grafting. Four months after grafting, the patient noticed two verrucous plaques in the grafted site (Fig. 1). She denied warts on any other body sites. There was no history of similar lesions in her family or close friends. The operator, who wore gloves, had a verrucous papule on his hand during the surgery. Skin biopsy of two different lesions, on the patients back and the operators hand, demonstrated histological features of verruca vulgaris. Human papillomavirus (HPV) typing was not performed. Although epidermal grafting appears to be an effective and safe method for the treatment of vitiligo, various complications have been reported, of which some are associated with the application of liquid nitrogen, such as postinflammatory hyperpigmentation, hypertrophic scarring, peripheral hypopigmentation and uneven pigmentation. Koebner phenomenon and recurrence have also been considered complications of epidermal grafting. The possibility of transmission of virus from patient to patient or from patient to doctor has been reported. One study showed that virus may survive on a cotton swab dipped into liquid nitrogen and suggested that virus transmission from patient to patient may occur via this route. Charles and Sire reported the possibility of transmission of papovavirus indirectly by cotton-tipped applicators which had been used earlier to treat verruca in other patients. In our case, the same liquid nitrogen and cotton-tipped applicators were not used for multiple patients. Bergbrant et al. reported that there is a risk of contamination of the operator by HPV DNA, during both carbon dioxide laser and electrocoagulation treatment. Once an individual has been infected, new warts may develop in sites of inoculation over a period of weeks to months. After experimental HPV inoculation, it requires from 2 to 9 months for a verruca to become clinically apparent. This observation implies a relatively long period of subclinical infection. In our patient, the verruca appeared 4 months after grafting. It is unclear whether the verruca vulgaris resulted from direct contact with the operators hand during the surgical procedure, or with another person after grafting. However, there are several possible mechanisms of viral transmission from the operator to the patient: the operator may have palpated the lesion with his bare hand immediately after cryosurgery to evaluate the effectiveness of the freezing, or transmission may have occurred during application of a dressing after surgery. We suggest that the risk of transmission of infection from doctor to patient should be considered as a new complication of epidermal grafting.