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Blumenthal, Signe Birgitta (2005): New insights into signaling pathways of salicylate and metalloporphyrins. Dissertation, LMU München: Fakultät für Chemie und Pharmazie



Aim of the study: I. Salicylate and heme oxygenase-1: The adhesion molecule P-selectin has been shown to be a major determinant of inflammatory responses. Different pharmacological agents including salicylate have been shown to inhibit IL-4-induced P-selectin expression in endothelial cells. Mechanisms responsible for P-selectin inhibition, however, are as yet not very well known. In the present work we confirmed this finding and aimed to elucidate the events leading to this inhibition. II. Metalloporphyrins and caspases: Apart from the beneficial effects of HO-1 on inflammatory processes, HO-1 is known to provoke anti-apoptotic effects. Metalloporphyrins are heme-analogous and are thus able to inhibit the activity of the heme-converting enzyme HO-1. Therefore, they are widely used and accepted tools in research investigating functional aspects of HO-1. In studies concerning the anti-apoptotic features of HO-1, different metalloporphyrins are often employed to either stimulate HO-1-expression or inhibit its activity. Apoptotic cell death is then quantified with various assay methods, such as the measurement of caspase-3-like activity. In an approach to determine potential anti-apoptotic features of ASA-induced HO-1 we observed contradictory results in a respective experimental setting. This led to the hypothesis that metalloporphyrins exert actions other than their well-known HO-1-dependent effects. Therefore, the second part of this work deals with the specificity of metalloporphyrins. Aim of the study was to find the cause for these contradictory results and further investigate a potential effect of the metalloporphyrins on caspase activity.