Modulation of allergic airway inflammation by glucocorticoids

Karabinskaya, Anna

dc.contributor.advisor	Reichardt, Holger Prof. Dr.
dc.contributor.author	Karabinskaya, Anna
dc.date.accessioned	2014-03-06T10:29:55Z
dc.date.available	2014-03-06T10:29:55Z
dc.date.issued	2014-03-06
dc.identifier.uri	http://hdl.handle.net/11858/00-1735-0000-0022-5E51-A
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4399
dc.identifier.uri	http://dx.doi.org/10.53846/goediss-4399
dc.language.iso	eng	de
dc.rights.uri	http://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subject.ddc	570	de
dc.title	Modulation of allergic airway inflammation by glucocorticoids	de
dc.type	doctoralThesis	de
dc.contributor.referee	Groß, Uwe Prof. Dr.
dc.date.examination	2013-09-19
dc.description.abstracteng	A crucial step in the development of improved drugs for asthma therapy is a thorough understanding of the mechanisms, which are important for effective treatment, and the identification of target cells in asthma pathogenesis. In this work these two key questions were tackled using a murine model of asthma. The analysis of the GC action mode revealed that the suppression of inflammation was strongly depended on DNA-binding and dimerisation of the GR. In absence of this molecular mechanism GC should no longer exert their anti-inflammatory functions in asthmatic mice despite the presence of the DNA-binding independent mode of GR action and non-genomic effects. Analysis of the efficiency of GC therapy in different cell type-specific GR-deficient mice surprisingly demonstrated that treatability of AAI was independent on GR expression in immune cells. This notion was corroborated by experiments with bone marrow chimeras of GRdim mice that revealed that the efficiency of GC therapy was mostly dependent on effects on non-immune cells of the lungs. Additionally, an inducible GR knockout in AT2 epithelial cells led to a strongly diminished effectiveness of GCs in the suppression of the inflammatory reaction. This observation correlates with the importance of these cells in the regulation of innate and adaptive immune responses and the initiation of asthmatic reactions. The gene expression analysis of GRdim mice, GRdim bone marrow chimeras and GRSPCcreERT2 mice showed that the treatment with GCs exerts its anti-inflammatory functions via downregulation of mRNA expression in lung cells of the following genes: IL-4 and IL-13, IL 1β and IL-33, IL-25 and RANTES, TSLP and TNF-α, Eotaxins (1&2) and iNOS. The expression of IL-9 and β-Tryptase could also be important for asthma treatment because of the activation of mast cells, but based on the efficient treatability of mast cell deficient mice, these genes do not seem to be crucial for GC therapy. The treatment reduced mRNA expression of genes critical for the DC activation and could improve the barrier function via upregulation of ZO-1 mRNA expression. These effects of GC on gene expression of several inflammatory mediators demonstrate how important the regulation of epithelial cell activation is during asthmatic reaction. Taken together the results of this work demonstrate that the suppression of AT2 cells and other structural cells of the lungs could be critical targets for asthma therapy by GCs and that the effects of GCs are mediated by the DNA-binding dependent mode of GR action. This information could become interesting for the development of new anti-asthmatic drugs that selectively inhibit crucial aspects of epithelial-immune or the epithelial-mesenchymal interactions.	de
dc.contributor.coReferee	Tuckermann, Jan Prof. Dr.
dc.contributor.thirdReferee	Hahn, Heidi Prof. Dr.
dc.contributor.thirdReferee	Alves, Frauke Prof. Dr.
dc.contributor.thirdReferee	Jarry, Hubertus Prof. Dr.
dc.contributor.thirdReferee	Walter, Lutz Prof. Dr.
dc.subject.eng	Glucocorticoids	de
dc.subject.eng	Asthma	de
dc.subject.eng	AAI	de
dc.subject.eng	AT2	de
dc.subject.eng	transactivation	de
dc.subject.eng	transrepression	de
dc.subject.eng	Therapy	de
dc.subject.eng	GRdim	de
dc.subject.eng	GRSPCcreERT2	de
dc.subject.eng	bone marrow chimera	de
dc.identifier.urn	urn:nbn:de:gbv:7-11858/00-1735-0000-0022-5E51-A-7
dc.affiliation.institute	Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)	de
dc.subject.gokfull	Biologie (PPN619462639)	de
dc.identifier.ppn	780018281

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Das Dokument erscheint in:

GGNB - Göttinger Graduiertenzentrum für Neurowissenschaften, Biophysik und molekulare Biowissenschaften [1115]
GGNB - Göttingen Graduate Center for Neurosciences, Biophysics and Molecular Biosciences

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