Dokument: Unraveling the mechanisms of EGFR-inhibitor associated cutaneous adverse effects.
| Titel: | Unraveling the mechanisms of EGFR-inhibitor associated cutaneous adverse effects. | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=14943 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20100427-104027-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Buhren, Bettina Alexandra [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Homey, Bernhard [Gutachter] Prof. Dr. Willbold, Dieter [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Recently, antagonists directed against the epidermal growth factor receptor (EGFR) have been successfully established in the treatment of cancer. Papulopustular rashes often accompanied by bacterial superinfections are considered the most prominent and most frequent adverse effects related to these targeted cancer drugs. Despite their clinical relevance the underlying molecular and cellular mechanisms of these adverse events have remained largely elusive. In the present study, the molecular and cellular mechanisms underlying EGFR-inhibitor (EGFR-I) associated cutaneous adverse events were analyzed. First, the inflammatory infiltrate and microbial colonization of EGFR-I induced rashes were systematically characterized and subsequently, the expression of chemokines and antimicrobial peptides in the presence or absence of EGFR-I was assessed in vitro and in vivo.
The inflammatory infiltrate of early stages of EGFR-I-induced skin eruptions is dominated by CD1a+ Langerhans cells, CD68+ macrophages, and CD4+ T lymphocytes. In addition, the skin eruptions frequently showed a marked colonization with Staphylococcus aureus (S. aureus). Correspondingly, EGFR-I selectively induced the expression of proinflammatory and skin-associated chemokines (CCL5, CCL27, and CXCL14) in human primary keratinocytes while the production of antimicrobial peptides (LL37, HBD3, RNAse7) was significantly suppressed. Functional analyses confirmed that conditioned media of EGFR-I treated keratinocytes expose a strong chemotactic potential on relevant leukocyte subsets. Moreover, the retinoid isotretinoin was able to suppress the EGFR-I induced chemokine production in vitro. The findings suggest a dual role for the EGFR at the interface between the host and the environment controlling inflammation and sustaining host defense within epithelial surfaces. Based upon the results of this thesis a novel model for the mechanisms of action of EGFR-I induced cutaneous adverse effects is proposed combining the induction of proinflammatory chemokines on the one and the suppression of antimicrobial peptides on the other hand. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 27.04.2010 | |||||||
| Dateien geändert am: | 21.04.2010 | |||||||
| Promotionsantrag am: | 12.12.2009 | |||||||
| Datum der Promotion: | 29.01.2010 |
