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Comparison of growth-inhibitory agents by fluorescence imaging of human skin re-epithelialization in vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
2006 (English)In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 86, no 4, 292-299 p.Article in journal (Refereed) Published
Abstract [en]

Drug screening procedures should preferably utilize experimental settings mimicking the in vivo situation. The aim of this study was to evaluate a skin explant model as a tool to identify topical agents with anti-proliferative properties in human epidermis. Re-epithelialization was initiated from a skin punch biopsy explanted onto de-epidermized dermis and cultured at the air-liquid interface in the presence of the epidermal growth factor receptor kinase inhibitor PKI166, tacrolimus or established topical anti-psoriatic drugs: betamethasone, calcipotriol, dithranol and tazarotene. Neo-epidermal extension was traced by fluorescence microscopy prior to histomorphometric analysis. PKI166 at 1 mu M decreased the mean radial outgrowth rate (-19%), frequency of BrdU-positive (-37%) and laminin 5-positive (-45%) cells, indicating reduced proliferation and migration of neo-epidermal keratinocytes. However, the papillomatosis index and epithelial thickness were not significantly affected. Calcipotriol at 1 mu M had a similar effect on the outgrowth rate (-15%) and fraction of laminin 5-stained keratinocytes (-40%). Furthermore, calcipotriol significantly reduced mean neo-epidermal thickness. Equimolar concentrations of the other test compounds had no apparent effect on histology or outgrowth parameters. This study exemplifies the versatility of combined dynamic and morphological analysis and emphasizes the potential of epidermal growth factor receptor-directed inhibition in hyperproliferative disorders of the epidermis.

Place, publisher, year, edition, pages
2006. Vol. 86, no 4, 292-299 p.
Keyword [en]
epidermal growth factor, tyrosine kinase inhibitors, proliferation, epidermis, fluorescent tracer
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-89155DOI: 10.2340/00015555-0089ISI: 000239602200001PubMedID: 16874412OAI: oai:DiVA.org:uu-89155DiVA: diva2:159461
Available from: 2004-01-01 Created: 2004-01-01 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Human Epidermal Growth Factor Receptors and Biological Effects of HER-directed Molecules on Skin Epithelialization
Open this publication in new window or tab >>Human Epidermal Growth Factor Receptors and Biological Effects of HER-directed Molecules on Skin Epithelialization
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Human skin forms a biologically active barrier and maintains vital protective functions through continuous regeneration of cells within its outermost layer, the epidermis. In healthy skin, renewal of epithelial cells is a tightly regulated process in which the epidermal growth factor receptor (EGFR or HER1) and its various ligands are involved. The biological role of other EGFR family members (HER2–4) in normal and diseased human skin has gained less interest. The purpose of this work was to investigate the expression and contribution of different HERs in cultured epidermis and psoriatic skin.

Epidermal regeneration was studied by fluorescence imaging of a skin explant model exposed to anti-psoriatic drugs, HER ligands or HER-blocking molecules. EGFR, HER2 and HER3 were all markedly expressed with an in vivo-like immunostaining pattern in cultured neoepidermis, whereas only low amounts of HER4 were detected at protein and mRNA levels. Re-epithelialization was associated with receptor activation. Application of HER-selective tyrosine kinase inhibitors and monoclonal antibodies reduced the proliferative activity, receptor phosphorylation and radial outgrowth from normal skin explants. Similar anti-dynamic effects were obtained with HER kinase inhibition of neoepidermis generated from psoriatic skin. Among the HER receptors, EGFR seemed to be the dominant subtype during epithelialization in vitro although HER2 and HER3 were also involved. HER2 probably functioned as a co-receptor for the kinase-deficient HER3 in neoepidermis. In vivo, expression of HER4 mRNA was detected in normal and uninvolved psoriatic skin but was virtually absent in lesional skin, a potentially important finding for HER signalling in psoriasis.

This thesis demonstrates the utility of combined dynamic and biochemical analyses of re-epithelialization and highlights the role of EGFR and other HERs for epidermal growth. It also underscores the potential of HER-directed inhibition to control hyperproliferative states of the epidermis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 424
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-89154 (URN)978-91-554-7426-3 (ISBN)
Public defence
2009-03-20, Enghoffsalen, Akademiska Sjukhuset, Ingång 50, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2009-02-26 Created: 2004-01-01 Last updated: 2011-06-29Bibliographically approved

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Forsberg, SofiRollman, Ola

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