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The role of new pro-inflammatory and/or pro-fibrotic molecules in the pathogenesis of systemic sclerosis.
Tomčík, Michal ; Bečvář, Radim (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Systemic sclerosis (SSc) is a generalized connective tissue disease affecting the skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. To date, none of the tested drugs have demonstrated convincing efficacy in the treatment of SSc. S100A4 is involved in the regulation of cell motility, proliferation, apoptosis, angiogenesis and remodeling of the extracellular matrix. It was originally described as a promoter of metastasis in tumors, however, its pro-inflammatory properties have recently been demonstrated in inflammatory rheumatic diseases. The aim of this study was to assess the role of S100A4 in pathological activation of fibroblasts in SSc and in experimental models of dermal fibrosis. Results: The expression of S100A4 was increased in the skin of SSc patients, in SSc fibroblasts and in experimental fibrosis in a TGF-β / Smad dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, inhibition of S100A4 or its complete deficit abrogated the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4 knock-out mice (S100A4-/- ) were protected from bleomycin-induced skin fibrosis with reduced dermal thickening,...
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The role of new profibrotic molecules in the pathogenesis of systemic sclerosis.
Šumová, Barbora ; Šenolt, Ladislav (advisor) ; Funda, David (referee) ; Soukup, Tomáš (referee)
Systemic sclerosis (SSc) is immune-mediated fibrotic disease of unknown aetiology. Among the dominant pathogenic manifestations of SSc belong vascular changes, production of autoantibodies, activation of innate and adaptive immune responses and fibrotic processes. Transforming growth factor beta (TGF-β) has been identified as a central profibrotic factor stimulating fibroblasts to produce collagen. There are, however, a number of other mediators involved in the pathogenesis of SSc. Mutual activation and amplification of these molecules and their cascades may be a central mechanism of the SSc pathogenesis. Hedgehog (Hh) canonical signalling pathway plays an important role in the development and progression of fibrotic diseases. Expression of Hh target genes can be regulated through a canonical or non-canonical signalling cascade. The non-canonical activation of GLI transcription factors by TGF-β has not yet been investigated in SSc. The substantial part of this thesis is focused on the study of the mutual interaction of TGF-β and Hh signalling pathway. In vitro analysis confirmed TGF- β/SMAD3 dependent activation of GLI2 in dermal fibroblasts. Fibroblasts specific knockout of GLI2 prevented the development of experimental fibrosis in vivo. Combined targeting of canonical and non-canonical Hh...
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New biomarkers and candidate molecules in antifibrotic therapy in systemic scleroderma
Štorkánová, Hana ; Tomčík, Michal (advisor) ; Javorková, Eliška (referee)
Systemic scleroderma (SSc) is a systemic connective tissue disease affecting skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. No agent has been proven effective in the treatment of SSc. There is a lack of suitable biomarkers for monitoring the disease activity or the response to the treatment of SSc. Therefore our aim was to analyse the extracellular levels of S100A4, Hsp90 (Heat shock protein 90) and IL-35 (interleukin-35) in SSc. S100A4 and Hsp90 have been initially studied in tumours; in some of them considered as suitable prognostic markers and candidates for future therapies. We have recently described the profibrotic role of S100A4 and Hsp90 in the pathogenesis of SSc. Our results showed that inactivation of S100A4 and Hsp90 effectively prevented the development of experimental skin fibrosis. This was consequently confirmed by the analysis of S100A4 and Hsp90 in the peripheral blood of patients with SSc, where significant associations with disease activity and organ involvement were detected. IL-35 may become another potential biomarker of SSc. We detected increased expression of IL-35 in the affected skin, dermal fibroblasts and in serum of patients with SSc. Moreover, the main profibrotic mediator transforming growth factor...
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The role of new pro-inflammatory and/or pro-fibrotic molecules in the pathogenesis of systemic sclerosis.
Tomčík, Michal ; Bečvář, Radim (advisor) ; Hrnčíř, Zbyněk (referee) ; Horák, Pavel (referee)
Introduction: Systemic sclerosis (SSc) is a generalized connective tissue disease affecting the skin and internal organs. The pathogenesis of SSc is characterized by inflammation, vasculopathy and fibrosis. To date, none of the tested drugs have demonstrated convincing efficacy in the treatment of SSc. S100A4 is involved in the regulation of cell motility, proliferation, apoptosis, angiogenesis and remodeling of the extracellular matrix. It was originally described as a promoter of metastasis in tumors, however, its pro-inflammatory properties have recently been demonstrated in inflammatory rheumatic diseases. The aim of this study was to assess the role of S100A4 in pathological activation of fibroblasts in SSc and in experimental models of dermal fibrosis. Results: The expression of S100A4 was increased in the skin of SSc patients, in SSc fibroblasts and in experimental fibrosis in a TGF-β / Smad dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, inhibition of S100A4 or its complete deficit abrogated the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4 knock-out mice (S100A4-/- ) were protected from bleomycin-induced skin fibrosis with reduced dermal thickening,...
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