| dc.contributor.advisor | Oppermann, Martin Prof. Dr. | |
| dc.contributor.author | Reichardt, Sybille D. | |
| dc.date.accessioned | 2015-04-14T10:32:39Z | |
| dc.date.available | 2015-04-14T10:32:39Z | |
| dc.date.issued | 2015-04-14 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-5FB2-6 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5026 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Physiological and molecular features of glucocorticoid actions in the gastrointestinal tract | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Oppermann, Martin Prof. Dr. | |
| dc.date.examination | 2015-03-24 | |
| dc.description.abstracteng | Ever since their first successful application in the treatment of RA patients in the late 1950, GCs have been the gold standard for the treatment of multiple inflammatory and neoplastic diseases. There are, however, also severe adverse effects that denote restrictions upon the use of GCs. In particular oral application of GCs can lead to gastrointestinal complications that may severely affect the patient’s quality of life and lead to a reduced tolerability of the therapy. In this work I have described and characterized gastroparesis as a so far unrecognized effect of GCs in the gastrointestinal tract that is mediated via trans-activation of genes. Changes in gene expression characteristic for M2 macrophage polarization proved to be unrelated to gastroparesis. Similarly, an involvement of two genes specifically expressed in the gastrointestinal tract could be ruled out. In contrast, I could confirm that genes related to the regulation of NO production contribute to gastroparesis. A decrease in iron availability through up-regulation of Lcn2 was found to partially impact on gastric motility whereas reduced substrate availability for NO synthesis through up-regulation of Arg2 proved to be responsible for impaired gastric emptying. Hence, GC therapy causes gastroparesis by increasing gene expression in the stomach in a DNA-binding-dependent manner thereby diminishing the availability of NO required for gastric motility. Complete prevention of gastroparesis was achieved by an exogenous supply of L-arginine thus providing a means to overcome the observed effect with the help of a dietary supplement. My study also offers a possible explanation for the anti-emetic effect of GCs that has been used for long to interfere with CINV without knowing the underlying mechanism. Now it appears likely that reducing NO availability in the stomach is the way how GCs counteract CINV, which is accompanied by increased NO production. Unfortunately, further elucidation of this process is impossible in rodent models due to the inability of mice and rats to vomit. Taken together, the identification and characterization of GC-induced gastroparesis sheds new light on both adverse and beneficial activities of GCs in the stomach and may help to optimize therapy in the future for the patients’ benefit. | de |
| dc.contributor.coReferee | Dobbelstein, Matthias Prof. Dr. | |
| dc.subject.eng | Glucocoticoids | de |
| dc.subject.eng | gastroparesis | de |
| dc.subject.eng | nitric oxide | de |
| dc.subject.eng | arginase | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5FB2-6-5 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | Immunologie / Allergologie / Umweltmedizin / Medizinische Ökologie - Allgemein- und Gesamtdarstellungen (PPN619875445) | de |
| dc.identifier.ppn | 822045443 | |