Evaluation of beneficial and adverse effects of glucocorticoids on a newly developed full-thickness skin model

• Published in: Toxicology in vitro 2008-04, Vol.22 (3), p.747-759
• Main Authors: Zöller, Nadja Nicole, Kippenberger, Stefan, Thaçi, Diamant, Mewes, Karsten, Spiegel, Martina, Sättler, Andrea, Schultz, Maike, Bereiter-Hahn, Jürgen, Kaufmann, Roland, Bernd, August
• Format: Article
• Language: English
• Subjects: Administration, Topical; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - toxicity; Apoptosis - drug effects; Atrophy; Biomarkers; Cell Proliferation - drug effects; Child, Preschool; Collagen - biosynthesis; Cytokines - metabolism; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Fibroblasts - drug effects; Fibroblasts - metabolism; Glucocorticoid; Glucocorticoids - pharmacology; Glucocorticoids - toxicity; Humans; In Situ Nick-End Labeling; In Vitro Techniques; Inflammation; Interleukin-6 - metabolism; Interleukin-8 - metabolism; Irradiation; Keratinocytes - drug effects; Keratinocytes - metabolism; Ointments; Skin - drug effects; Skin - pathology; Skin - radiation effects; Skin model; Ultraviolet Rays; UVB
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2007.11.022

Glucocorticoids (GCs) are highly effective compounds widely used in the treatment of inflammatory diseases; however, they offer distinct adverse effects such as skin thinning in response to long-term topical treatment. Nevertheless it is difficult to deduce the safety of a newly synthesized compound from its structural formula. Efficient assay systems that measure beneficial and adverse effects are needed. In the present study the applicability of a three-dimensional full-thickness skin model (FTSM) is tested to display GC-induced effects regarding anti-inflammation and atrophy. It is shown that topical application of a commercial GC ointment suppresses the ultraviolet (UV)B induced induction of interleukin (IL)-6 and IL-8. Addition of purified betamethasone-17-valerate, prednicarbate and clobetasol-17-propionate to the culture medium for 14days caused a reduction in the number of epidermal cell-layers corresponding to the atrophic risk found in vivo. Similarly, repeated topical application of five GC creams induced epidermal thinning. Evidence is given that the inhibitory effect on keratinocyte proliferation contributes to this effect. Furthermore, dermal thinning was monitored by measuring type I collagen synthesis; a decreased collagen synthesis similar to the in vivo situation is shown. The present study demonstrates the versatility of this FTSM in the validation of effectiveness and safety of GCs.