Lorraine H. Kligman’s research while affiliated with University of Pennsylvania and other places

The generation of reactive oxygen species (ROS) by ultraviolet radiation (UVR) accelerates skin aging, which is known as photoaging. Because cutaneous iron catalyzes ROS generation, sequestering iron by chelating agents is thought to be an effective approach toward preventing photoaging. Previously, N-(4-pyridoxylmethylene)-l-serine (PYSer) was designed as an antioxidant to suppress iron-catalyzed ROS generation by its iron-sequestering activity. In this study, PYSer showed protective effects against skin damage in hairless mice irradiated with ultraviolet B (UV-B). Topical application of PYSer to the skin significantly delayed and/or decreased the visible wrinkle formation induced by chronic UV-B irradiation. A histological study indicated that UV-B–induced epidermal hypertrophy and lymphocytic infiltration were suppressed by PYSer. Moreover, PYSer showed suppressive activity against the UV-B–induced increase in glycosaminoglycans (GAG). These results indicate that PYSer is a promising antioxidant for the prevention of chronic skin photoaging by its iron-sequestering activity.

Wrinkles induced in hairless mice with UVB radiation were treated with Zyderm and Zyplast injectable collagen implants. Image analysis of latex casts taken before and after implantation showed that wrinkle effacement was maintained during the 2–4-week period of the experiment. Histological examination of biopsies of implant sites demonstrated collagen implants that were well colonized by fibroblasts yet were quite free of inflammatory infiltrates. These findings suggest that the injectable collagen implants were well tolerated by the photodamaged skin.

Abstract In previous studies with albino hairless mice, we showed that broadband ultraviolet A radiation (UVA) damages dermal connective tissue. Recent studies examined segments of the UVA waveband in detail. In one, mice were irradiated with a solar simulator using Schott WG filters with different 50% cutoff points in the UVA region. Biopsies were examined at the following dosages: WG 335 (500,1000, 2000 J/cm2); WG 345 (800,1600,3200 J/cm2); WG 360 (2000,4000 J/cm2). A second study utilized a high-intensity source filtered to eliminate wavelengths < 340 nm. Biopsies were examined at 500,1000, 2000,4000, and 8000 J/cms2. Histochemical stains were used to examine elastic fibers, collagen, and glycosaminoglycans. Collagen appeared damaged mainly by the shorter wavelengths, while all wavelengths induced elastic fiber hyperplasia and increased glycosaminoglycans. These changes required high but realistically obtainable doses. UVA is a weak carcinogen but in a third study its addition to low-dose UVB caused significant enhancement of tumorigenesis.

The generation of reactive oxygen species (ROS) by ultraviolet radiation (UVR) accelerates skin aging, which is known as photoaging. Because cutaneous iron catalyzes ROS generation, sequestering iron by chelating agents is thought to be an effective approach toward preventing photoaging. Previously, N-(4-pyridoxylmethylene)-l-serine (PYSer) was designed as an antioxidant to suppress iron-catalyzed ROS generation by its iron-sequestering activity. In this study, PYSer showed protective effects against skin damage in hairless mice irradiated with ultraviolet B (UV-B). Topical application of PYSer to the skin significantly delayed and/or decreased the visible wrinkle formation induced by chronic UV-B irradiation. A histological study indicated that UV-B-induced epidermal hypertrophy and lymphocytic infiltration were suppressed by PYSer. Moreover, PYSer showed suppressive activity against the UV-B-induced increase in glycosaminoglycans (GAG). These results indicate that PYSer is a promising antioxidant for the prevention of chronic skin photoaging by its iron-sequestering activity.

Melanomas have been induced in hamsters and guinea pigs with short-term, low dose applications of dimethylbenz [a]anthracene (DMBA) alone. In mice, however, melanoma induction has required either croton oil or ultraviolet radiation promotion in addition to DMBA. In this study, we report the development of a malignant melanoma, with metastases, in a hairless mouse after six applications of 0.25% DMBA alone. At sacrifice, a large primary tumour with characteristics of intralesional transformation was present, along with numerous pigmented macules and papules. Metastases were present in lymph nodes and lungs. There was a marked similarity between this melanoma and its precursor lesions and those seen in an earlier, Weiser-Maple guinea pig model, which, in turn, resembled human melanoma.

SPARC is a matricellular protein involved in cell-matrix interactions. From expression patterns at the wound site and in vitro studies, SPARC has been implicated in the control of wound healing. Here we examined the function of SPARC in cutaneous wound healing using SPARC-null mice and dermal fibroblasts derived from them. In large (25 mm) wounds, SPARC-null mice showed a significant delay in healing as compared to wild-type mice (31 days versus 24 days). Granulation tissue formation and extracellular matrix protein production were delayed in small 6 mm SPARC-null wounds initially but were resolved by day 6. In in vitro wound-healing assays, while wild-type primary dermal fibroblasts showed essentially complete wound closure at 11 hours, wound closure of SPARC-null cells was incomplete even at 31 hours. Addition of purified SPARC restored the normal time course of wound closure. Treatment of SPARC-null cells with mitomycin C to analyze cell migration without cell proliferation showed that wound repair remained incomplete after 31 hours. Cell proliferation as measured by 3H-thymidine incorporation and collagen gel contraction by SPARC-null cells were not compromised. A significant delay in healing large excisional wounds and setback in granulation tissue formation and extracellular matrix protein production in small wounds establish that SPARC is required for granulation tissue formation during normal repair of skin wounds in mice. A defect in wound closure in vitro indicates that SPARC regulates cell migration. We conclude that SPARC plays a role in wound repair by promoting fibroblast migration and thus granulation tissue formation.

It is well known that photoaged skin is characterized by increases in dermal matrix components that include glycosaminoglycans, proteoglycans and masses of abnormal elastic fibers accompanied by substantial collagen loss. Histochemical staining of such tissue gives the impression of “massive” loss of collagen and its replacement by these other matrix components. Early biochemical studies have lent support to this notion with a reported decrease in total collagen of ∼45% compared to protected skin. More recent studies report considerably less, but varying, amounts of collagen loss. Rarely have the two approaches, histochemistry and biochemical analysis, been used in the same study to examine the same tissue. In this study, collagen loss was quantified biochemically in paired biopsies from sun-protected and sun-exposed arm skin of moderately photoaged female subjects (age 51–77 years). The values obtained were compared with histochemical and immunochemical findings. Quantitatively, collagen loss on a per mg protein basis was small compared to the histochemical appearance.

BACKGROUND: All-trans-retinol was the first vitamin to be synthesized in the laboratory. Dermatologic research with this agent, first begun in the 1960s, was discontinued because of its instability. Investigations since then have focused primarily on a metabolite of vitamin A, all-trans-retinoic acid, for the treatment of various dermatological disorders. TREATMENT: While topically applied retinoic acid is effective in reducing the signs of intrinsic aging and repairing photodamaged skin, depending on the concentration it causes a number of irritant effects, including erythema, peeling, dryness, and pruritus in some patients. This drawback stimulated renewed efforts to find a less irritating retinoid. ADVANCES: As a result of advances in the cosmetic industry, retinol is now being produced in a stable formulation, and is again commanding the attention of investigators. CONCLUSION: Clinical trials conducted so far indicate that, like retinoic acid, retinol can induce changes that have a beneficial effect on the epidermis but with decreased irritation.

The recognition that excessive exposure to sunlight can damage skin has been with us since antiquity.

We have proposed that UV activation of cytokine and integrin signaling pathways may initiate the photoaging process and that one of the effects of tretinoin treatment may be to alter the cytokine and integrin patterns. In previous results, steady-state mRNA levels of interleukin-1alpha, tumor necrosis factor alpha, transforming growth factor beta, collagenase, stromelysin, collagen, and integrins (alpha1 and alpha2) were increased in the skin of hairless mice that were either UV treated or concurrently treated with UV followed by topical tretinoin for 5 weeks. The aim of this study was to focus on the expression of alpha1, alpha2 and alpha5 integrins, IL-1alpha, IL-1beta, cJun, and cFos at an earlier time point (3 weeks). Animals were UV irradiated thrice weekly for 3 weeks and were treated topically with either 0.05% tretinoin or the vehicle immediately after each exposure. Total RNA was prepared and used in RT-PCR with radiolabeled dCTP and specific primers. UV slightly increased steady-state mRNA levels for alpha1, alpha2 and alpha5 integrins whereas UV + tretinoin increased their expression (3-, 2- and 7-fold respectively). Steady-state mRNA levels for IL-1alpha, IL-1beta and cJun were increased with UV (3-, 12- and 6-fold respectively) and with UV + tretinoin (6-, 7- and 9-fold respectively). In contrast, cFos expression was unchanged. In situ staining for IL-1alpha mRNA was slightly more abundant in mice treated for 3 weeks with UV and UV + tretinoin than in controls whereas 5 weeks of UV + tretinoin treatment gave strongly positive staining. Results are consistent with cytokines and integrins mediating the effects of UV on the skin, with modulation of these effects by tretinoin.