Holdings: Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis

Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis:

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Main Author:	Do, Nhu-Nguyen (Author)
Format:	Thesis Book
Language:	English
Published:	Köln 2017
Subjects:	Hochschulschrift
Online Access:	Inhaltsverzeichnis Inhaltsverzeichnis
Physical Description:	91 Seiten Illustrationen 21 cm

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adam_text	TABLE OF CONTENT ZUSAMMENFASSUNG SUMMARY TABLE OF FIGURES TABLE OF TABLES 1 INTRODUCTION.................................................................................................................. -1 - 1.1 SKIN ARCHITECTURE AND FUNCTION ............................................................................. -1 - 1.1.1 EXTRACELLULAR MATRIX.......................................................................................- 2 - 1.2 SKIN FIBROSIS........................................................................................................... - 5 - 1.2.1 CUTANEOUS WOUND HEALING IN PHYSIOLOGY..................................................- 5 - 1.2.2 IMPAIRED WOUND HEALING AND PATHOLOGICAL FIBROTIC RESPONSES .............. - 7 - 1.2.3 MOUSE MODEL OF BLEOMYCIN-INDUCED SKIN FIBROSIS ................................... - 8 - 1.2.4 THE ROLE OF MACROPHAGES IN SKIN REPAIR AND FIBROSIS ............................. - 9 - 1.3 MACROPHAGES.......................................................................................................-10- 1.3.1 MACROPHAGE ORIGIN AND IDENTIFICATION......................................................-1 0 - 1.3.2 MACROPHAGE FUNCTION .................................................................................. -11- 1.3.3 MACROPHAGE ACTIVATION AND NOMENCLATURE ............................................ -1 2 - 1.3.4 TOLL-LIKE RECEPTOR 4 SIGNALING-MEDIATED INFLAMMATORY RESPONSE ........... -1 3 - 1.4 CYTOKINES, GROWTH FACTORS AND THEIR SIGNALING PATHWAYS ............................ -1 4 - 1.4.1 P38A M ARK................................................................................................. -14- 1.4.2 SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 (STAT3) .................... -15- 1.4.3 TRANSFORMING GROWTH FACTOR SS (TG FSS)......................................................- 20 - 2 AIMS............................................................................................................................. -23- 3 RESULTS.........................................................................................................................-24- 3.1 EFFICIENT GENE DELETION AND IMPAIRED PROTEIN ACTIVATION IN P38AMKO OR STAT3MKO MICE 3.2 SKIN INJURY AND ACUTE WOUND HEALING MOUSE MODEL -24- -26- 3.2.1 MYELOID CELL-RESTRICTED P38A DEFICIENCY HAS NO MAJOR IMPACT ON WOUND MORPHOLOGY AND KINETICS OF SKIN REPAIR..................................................................- 26 - 3.2.2 MYELOID CELL-RESTRICTED STAT3 DEFICIENCY HAS NO MAJOR IMPACT ON WOUND MORPHOLOGY AND KINETICS OF SKIN REPAIR..................................................................- 32 - 3.3 BLEOMYCIN-INDUCED SKIN FIBROSIS MOUSE MODEL.............................................- 36 - 3.3.1 MYELOID CELL-SPECIFIC STAT3 DEFICIENCY ACCELERATES THE DEVELOPMENT OF BLEOMYCIN-INDUCED SKIN FIBROSIS .............................................................................. - 36 - 3.3.2 MYELOID CELL-RESTRICTED STAT3 DEFICIENCY INCREASES COLLAGEN DEPOSITION IN BLEOMYCIN-INDUCED FIBROTIC LESIONS..........................................................................- 37 - 3.3.3 ENHANCED FIBROSIS IN STAT3MK0 MICE IS CHARACTERIZED BY INCREASED SMAD2 PHOSPHORYLATION AND COMP EXPRESSION ............................................................... -41 - 3.3.4 MYELOID CELL-SPECIFIC STAT3 DEFICIENCY LEADS TO AUGMENTED MAST CELL NUMBERS AT THE FIBROTIC EDGE OF THE BLEOMYCIN-INDUCED LESION ......................... - 42 - 3.3.5 STAT3-DEFICIENT MACROPHAGES FROM THE FIBROTIC LESION ARE DIFFERENTLY ACTIVATED AND EXPRESS LESS ANTI-FIBROTIC MEDIATORS .............................................. - 44 - 3.3.6 DECORIN EXPRESSION IS NOT REDUCED IN THE OVERALL FIBROTIC LESION OF STAT3MKO MICE IN VIVO.................................................................................................................- 45 - 3.3.7 IL-10 INCREASES SOCS3 EXPRESSION AND REPRESSES TGFSS PRODUCTION IN BMDMS VIA STAT3 SIGNALING IN VITRO.........................................................................- 46 - 3.3.6 IL-10 STIMULATED MACROPHAGES CONTROL THE EXPRESSION OF CTGF IN FIBROBLASTS IN VITRO....................................................................................................... - 49 - 4 DISCUSSION.................................................................................................................... -50- 4.1 P38AMKO MICE SHOW AN INCREASED NUMBER OF NEUTROPHILS IN THE EARLY WOUND TISSUE, YET SHOW NO MAJOR WOUND HEALING PHENOTYPE.............................................- 50 - 4.2 STAT3MKO MICE HAVE DIFFERENTLY ACTIVATED WOUND MACROPHAGES, YET SHOW NO MAJOR WOUND HEALING PHENOTYPE ................................................................................. - 51 - 4.3 MYELOID CELL-RESTRICTED STAT3 DEFICIENCY ACCELERATES THE DEVELOPMENT OF BLEOMYCIN-INDUCED SKIN FIBROSIS .................................................................................. - 52 - 4.3.1 STAT3 RESTRICTS THE AUTOCRINE TGFSS LOOP IN MACROPHAGES, THUS LIMITING TGFSS AVAILABILITY AND PRO-FIBROTIC FIBROBLAST ACTIVATION ....................................... - 52 - 4.3.2 IMPAIRED DECORIN EXPRESSION IN MACROPHAGES DOES NOT REDUCE THE TOTAL AMOUNT OF DECORIN IN BLEOMYCIN-INDUCED FIBROTIC SKIN ........................................ - 54 - 4.3.3 ACCELERATED FIBROSIS DEVELOPMENT IN STAT3MK0 MICE IS INDEPENDENT FROM PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MACROPHAGES ................................... - 55 - 4.3.4 HOW MUCH DO ECM DEGRADATION AND PROTEOLYTIC ACTIVATION OF TGFSS CONTRIBUTE TO THE FIBROTIC PHENOTYPE?.....................................................................- 56 - 4.4 PERSPECTIVE...........................................................................................................-57- 5 MATERIALS AND METHODS.............................................................................................- 60 - 5.1 REAGENTS AND BUFFERS ........................................................................................ - 60 - 5.2 EXPERIMENTAL ANIMALS.........................................................................................- 61 - 5.2.1 MOUSE STRAINS (P38AMKO, STAT3MK0, TGFSSRIIMK0) ................................ -61 - 5.2.2 GENOTYPING................................................................................................... -61- 5.2.2.1 ISOLATION OF GENOMIC DMA.....................................................................- 61 - 5.2.2.2 P C R ......................................................................................................... -62- 5.2.3 WOUNDING..................................................................................................... -63- 5.2.3.1 FULL-THICKNESS SKIN EXCISIONAL WOUNDING...........................................- 63 - 5.2.3 2 BLEOMYCIN-INDUCED SKIN FIBROSIS......................................................... - 63 - 5.3 HISTOLOGY...............................................................................................................-64- 5.3.1 HISTOCHEMISTRY............................................................................................. -64- 5.3.2 I MM U NOHISTOCHEMISTRY................................................................................- 64 - 5.3.3 MORPHOMETRIC ANALYSIS................................................................................- 66 - 5.3.3.1 SIRIUS RED................................................................................................- 66 - 5.3.3.2 SECOND HARMONIC GENERATION MICROSCOPY ....................................... - 66 - 5.4 CELL ISOLATION FROM TISSUE................................................................................... - 67 - 5.4.1 FLUORESCENCE ACTIVATED CELL SORTING (FACS) ........................................... - 67 - 5.4.1 ISOLATION OF PRIMARY FIBROBLASTS..................................................................- 69 - 5.4.2 ISOLATION OF MACROPHAGES ( M 0 ) ................................................................- 69 - 5.4.2.1 PERITONEAL EXUDATE CELLS/ PERITONEAL MACROPHAGES ........................ - 69 - S.4.2.2 BONE-MARROW DERIVED MACROPHAGES (BM DM S) ............................. -6 9 5.5 CELL CULTURE...........................................................................................................- 70 5.5.1 CULTURE OF PRIMARY MACROPHAGES.............................................................-7 0 5.5.1 CULTURE OF PRIMARY FIBROBLASTS....................................................................- 71 5.5.2 TRANS-WELL CO-CULTURE OF MACROPHAGES AND FIBROBLASTS.......................-71 5.6 ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA) FOR TGFSS DETECTION ........ -7 2 5.7 RNA EXTRACTION, REVERSE TRANSCRIPTION PCR AND QRT-PCR........................- 72 5.8 WESTERN BLOT........................................................................................................ - 75 5.9 STATISTICAL ANALYSIS.............................................................................................. - 76 6 REFERENCES..................................................................................................................- 77 7 ABBREVIATIONS............................................................................................................. -8 6 6 ACKNOWLEDGEMENTS...................................................................................................- 90 9 EIDESSTATTLICHE ERKLAERUNG......................................................................................... - 91
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spelling	Do, Nhu-Nguyen Verfasser (DE-588)1125143614 aut Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis vorgelegt von Nhu-Nguyen Do Köln 2017 91 Seiten Illustrationen 21 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Universität zu Köln 2017 (DE-588)4113937-9 Hochschulschrift gnd-content B:DE-101 application/pdf http://d-nb.info/1131738160/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029865631&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Do, Nhu-Nguyen Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis
subject_GND	(DE-588)4113937-9
title	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis
title_auth	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis
title_exact_search	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis
title_full	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis vorgelegt von Nhu-Nguyen Do
title_fullStr	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis vorgelegt von Nhu-Nguyen Do
title_full_unstemmed	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis vorgelegt von Nhu-Nguyen Do
title_short	Functional consequences of myeloid cell-specific Stat3 activation in skin fibrosis
title_sort	functional consequences of myeloid cell specific stat3 activation in skin fibrosis
topic_facet	Hochschulschrift
url	http://d-nb.info/1131738160/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029865631&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT donhunguyen functionalconsequencesofmyeloidcellspecificstat3activationinskinfibrosis

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