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http://doi.org/10.25358/openscience-3865Full metadata record
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Riehl, Dennis | |
| dc.date.accessioned | 2017-04-06T16:35:17Z | |
| dc.date.available | 2017-04-06T18:35:17Z | |
| dc.date.issued | 2017 | |
| dc.identifier.uri | https://openscience.ub.uni-mainz.de/handle/20.500.12030/3867 | - |
| dc.description.abstract | Pulmonary fibrosis is characterized by a dysregulated accumulation of extracellular matrix components. This chronic and irreversible disease has a poor prognosis because of limited treatment options. In the presented work, the cellular processes and cytokine networks initiated by extracellular histones during bleomycin-induced pulmonary fibrosis were studied in mice. As the cellular sources of extracellular histones, neutrophils and non-hematopoietic cells were identified by using chimeric H2B-eGFP reporter mice. In addition, citrullinated extracellular histones derived from neutrophil extracellular traps (NETs) were reduced after depletion of neutrophils in Ly6GCre/iDTR mice. This transient depletion of Ly6G+ neutrophils during the early phase of bleomycin-induced pulmonary fibrosis protected from extracellular matrix accumulation (collagen I,V) and the infiltration of pro-fibrotic Th17 cells into the lungs. Furthermore, blockade of extracellular histones (anti-histone H4 antibodies) protected from collagen I,V accumulation as well as epithelial/endothelial to mesenchymal transition. The blocked extracellular histones also led to reduced stress-induced gene expression levels in T regulatory cells. Histones activated platelets, followed by release of TGFβ1 during ex vivo studies. Lower concentrations of TGFβ1 and less collagen I,V accumulation were noted in PF4Cre/TGFβ1flox/flox mice. TGFβ1 inhibited IL-27 production in macrophages in a TGFbRI and TGFbRII dependent manner. The influence of TGFbRII on the release of IL-27 during bleomycin-induced pulmonary fibrosis was shown in LysMCre/TbRIIflox/flox mice. IL-27 apparently exerted anti-fibrotic activities, since IL-27RA-/- mice were more prone to fibrosis. The molecular inhibition mechanism of TGFβ1 was further analyzed by several in vitro studies: TGFβ1 engaged multiple downstream proteins such as p38 MAPK, Tristetraprolin and IL-10. A central signaling molecule of TGFβ1, Smad3, was shown to bind directly to the il-27p28 and ebi3 promoter regions. This work identifies extracellular histones as central key players during experimental pulmonary fibrosis. The extracellular histones appear to skew the reciprocal balance of IL-27 and TGFβ1 by triggering the release of platelet-derived TGFβ1. These data set extracellular histones in the focus of the search for future treatment options for pulmonary fibrosis. | en_GB |
| dc.language.iso | eng | |
| dc.rights | InCopyright | de_DE |
| dc.rights.uri | https://rightsstatements.org/vocab/InC/1.0/ | |
| dc.subject.ddc | 570 Biowissenschaften | de_DE |
| dc.subject.ddc | 570 Life sciences | en_GB |
| dc.title | Extracellular histones promote pulmonary fibrosis by multicellular interactions | en_GB |
| dc.type | Dissertation | de_DE |
| dc.identifier.urn | urn:nbn:de:hebis:77-diss-1000012072 | |
| dc.identifier.doi | http://doi.org/10.25358/openscience-3865 | - |
| jgu.type.dinitype | doctoralThesis | |
| jgu.type.version | Original work | en_GB |
| jgu.type.resource | Text | |
| jgu.description.extent | 192 Seiten | |
| jgu.organisation.department | FB 04 Medizin | - |
| jgu.organisation.year | 2017 | |
| jgu.organisation.number | 2700 | - |
| jgu.organisation.name | Johannes Gutenberg-Universität Mainz | - |
| jgu.rights.accessrights | openAccess | - |
| jgu.organisation.place | Mainz | - |
| jgu.subject.ddccode | 570 | |
| opus.date.accessioned | 2017-04-06T16:35:17Z | |
| opus.date.modified | 2017-04-18T10:25:19Z | |
| opus.date.available | 2017-04-06T18:35:17 | |
| opus.subject.dfgcode | 00-000 | |
| opus.organisation.string | FB 04: Medizin: Centrum für Thrombose und Hämostase (CTH) | de_DE |
| opus.identifier.opusid | 100001207 | |
| opus.institute.number | 0463 | |
| opus.metadataonly | false | |
| opus.type.contenttype | Dissertation | de_DE |
| opus.type.contenttype | Dissertation | en_GB |
| jgu.organisation.ror | https://ror.org/023b0x485 | |
| Appears in collections: | JGU-Publikationen | |
Files in This Item:
| File | Description | Size | Format | ||
|---|---|---|---|---|---|
 | 100001207.pdf | 29.1 MB | Adobe PDF | View/Open |