695 research outputs found

    Intracellular tyrosine kinases as novel targets for anti-fibrotic therapy in systemic sclerosis

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    Tissue fibrosis is a major cause of death in SSc, but therapies that target selectively fibrosis are not yet available for routine clinical use. Recent pre-clinical studies suggest that selective tyrosine kinase inhibitors that target c-Abl, PDGF receptor or Src kinases might be promising targets for anti-fibrotic approaches. Dual inhibition of c-Abl and PDGF receptor by imatinib and nilotinib, and inhibition of Src kinases either selectively by SU6656 or in combination with c-Abl and PDGF by dasatinib exerted potent anti-fibrotic effects. Imatinib, nilotinib, dasatinib and SU6656 reduced dose-dependently the synthesis of extracellular matrix protein in human dermal fibroblasts in vitro and prevented fibrosis in the mouse model of bleomycin-induced skin fibrosis. Clinical data from patients with chronic myelogenous leukaemia suggest that imatinib, nilotinib and dasatinib are well tolerated. Based on the promising pre-clinical data, imatinib is currently evaluated in clinical trials for the treatment of fibrosis in SSc and trials with other tyrosine kinase inhibitors are in preparatio

    Criteria to select molecular targets for anti-fibrotic therapy

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    Tissue fibrosis is a major cause of morbidity and mortality in SSc. An increasing number of promising molecular targets for anti-fibrotic therapies have been described recently. However, the number of patients eligible for clinical trials is limited in SSc. The present article discusses criteria to select the most promising molecular targets for clinical trials in SSc. Based on consensus among experts, important criteria for the selection of molecular-based therapies were as follows: First, there should be strong experimental evidence that targeting the molecule of interest inhibits fibrosis. Optimally, the anti-fibrotic effects should be confirmed in at least two complementary animal models of SSc. Second, inhibitors of the molecule of interest should be clinically available. Third, clinical experience with the drug of interest in other diseases hastens the initiation of clinical trials and reduces the risk of unexpected side-effects. Finally, funding for clinical trials with the drug of interest in SSc should be available. We propose that the priority of novel targets for evaluation in clinical trials in SSc might be selected based on these consensus criteri

    Are tyrosine kinase inhibitors promising for the treatment of systemic sclerosis and other fibrotic diseases?

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    Tissue fibrosis causes organ failure and death in patients with systemic sclerosis (SSc), but clearly effective anti-fibrotic therapies are not available. The tyrosine kinase inhibitor (TKI) imatinib, which blocks the pro-fibrotic c-Abl kinase and PDGF receptor, is currently evaluated in clinical proof-of-concept trials for the treatment of patients with SSc. In experimental models, imatinib efficiently prevented and reduced tissue fibrosis. First clinical case studies demonstrated anti-fibrotic effects of imatinib in selected patients with SSc and other fibrotic diseases, and observational studies in sclerotic chronic graft-versus-host disease showed promising results. Besides imatinib, the two novel TKIs of c-Abl and PDGF receptor nilotinib and dasatinib have recently proven efficacy in experimental models of SSc. The potential of TKIs of the VEGF receptor (e.g., semaxinib, vatalanib, sutent, and sorafenib) and the EGF receptor (e.g., erlotinib, gefitinib, lapatinib, and canertinib) as anti-fibrotic treatments are also discussed in this review. Prior to clinical use, however, controlled trials need to address efficacy as well as tolerability of TKIs in patients with different fibrotic diseases

    Monocyte chemoattractant proteins in the pathogenesis of systemic sclerosis

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    Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of SSc. The molecular mechanisms underlying the infiltration of inflammatory cells into the skin and the subsequent activation of fibroblasts are still largely unknown. Chemokines are a family of small molecules that are classified according to the position of the NH2-terminal cysteine motif. Recent data indicate that chemokines and in particular two members of the subfamily of monocyte chemoattractant proteins, MCP-1 (CCL-2) and MCP-3 (CCL-7), might be involved in the pathogenesis of SSc. MCP-1 and -3 are overexpressed by SSc fibroblasts and in skin lesions from SSc patients compared to healthy controls. MCP-1 and -3 are chemotactic for inflammatory cells and stimulate their migration into the skin. In addition to their pro-inflammatory effects, MCP-1 and -3 contribute to tissue fibrosis by activating the synthesis of extracellular matrix proteins in SSc fibroblasts. Therapeutic strategies targeting MCP-1 have revealed promising results in several animal models of SSc. Antagonists against the receptor CCR2 are currently tested in clinical trials of a variety of diseases and also represent interesting candidates for target-directed therapy in SS

    Mechanisms of vascular damage in SScÔÇöimplications for vascular treatment strategies

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    Vascular abnormalities are a major component of SSc, but little is known about the events or mechanisms that initiate vascular injury and prevent its repair. In SSc, angiogenesis is incomplete or lacking despite the increased expression of a large array of pro-angiogenic factors such as VEGF. Conflicting results have recently been published concerning the presence and role of vasculogenesis and circulating endothelial progenitor cells in SSc. It remains to be established if these endothelial progenitor cells are a marker of endothelial disease or a cause of insufficient vascular repair. Human mesenchymal stem cells (MSCs) may be an alternative source for endothelial progenitor cells, and it has been observed that the angiogenic potential of endothelial-like MSCs is reduced. Other mechanisms of vascular damage include oxidative stress and factors released from activated platelets. In addition, growth factors such as ET-1 and PDGF induce proliferation of vascular smooth muscle cells resulting in intimal thickening. For the development of new therapeutic strategies, it is important to realize that the different vascular pathologiesÔÇöuncompensated loss of capillaries on one hand and vascular remodelling with a proliferative vasculopathy on the otherÔÇömight require different treatment approache

    S.6.1ÔÇâ╬▓-catenin is a central mediator in SSc

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    Background. ╬▓-catenin is the central integrator of canonical Wnt signalling. Since recent evidence suggests a central role of Wnts in fibrosis, we examined the ╬▓-catenin/Wnt pathway in SSc and focused on the role of ╬▓-catenin in fibroblast activation. Methods. We performed qPCR for several Wnt ligands and axin-2 to examine Wnt expression in SSc skin. We further studied protein levels of Wnt-1, -4, -10b and ╬▓-catenin by IHC. To establish the effects of ╬▓-catenin/Wnt signalling on collagen release, we created mice with fibroblast-specific stabilization of ╬▓-catenin (dEx3 ╬▓-catenin (wt/fl) ├Ś Col1a2; Cre-ER) as well as mice carrying fibroblast-specific deletion of ╬▓-catenin [Ctnnb1(fl/fl) ├Ś Col1a2; Cre-ER]. Summary of the results. We could demonstrate mRNA overexpression of Wnt-1, -2, -9a, -9b, -10a, -10b and -16 in SSc skin. Wnt-1, -4 and -10b consistently showed strong expression in SSc skin when compared with healthy skin. On protein level, however, Wnt-4 was indistinguishable between SSc patients and healthy controls, whereas Wnt-1 and Wnt-10b protein levels were increased in SSc skin. The overexpression of Wnt-1 and Wnt-10b resulted in a prominent nuclear accumulation of ╬▓-catenin in fibroblasts. Finally, increased mRNA levels of the target gene axin-2 confirmed the activation of canonical Wnt signalling. In dEx3 ╬▓-catenin (wt/ex) mice, we addressed the consequences of enhanced Wnt signalling and increased accumulation of ╬▓-catenin in SSc. We selectively targeted ╬▓-catenin in fibroblasts. Cre-activated dEx3 ╬▓-catenin (wt/fl) ├Ś Col1a2; Cre-ER mice showed massive and spontaneous dermal thickening even 2 weeks after Cre activation. Eight weeks after Cre-activation, skin thickening cumulated at 102.6% (P < 0.001). In line with the dermal thickening, hydroxyproline content and myofibroblast counts showed strong increases. To test the therapeutic potential of targeting ╬▓-catenin/Wnt signaling, we created Ctnnb1(fl/fl) x Col1a2;Cre-ER mice to specifically delete ╬▓-catenin in fibroblasts. After Cre activation and ╬▓-catenin deletion in fibroblasts, mice were challenged with bleomycin subcutaneously for 4 weeks. We found that Cre-activated Ctnnb1(fl/fl) ├Ś Col1a2; Cre-ER mice were protected from bleomycin-induced dermal with a reduction of skin thickening by 71% (P < 0.05). Conclusions. We demonstrated a prominent activation of canonical Wnt signalling in SSc with nuclear accumulation of ╬▓-catenin in fibroblasts and activation of the target gene axin-2. Our results showed that fibroblast-specific stabilization of ╬▓-catenin resulted in enhanced collagen release, whereas deletion of ╬▓-catenin potently reduced collagen production. Together, our findings highlight a key role of ╬▓-catenin in fibroblast activation and fibrosis. Thus, ╬▓-catenin may be promising molecular target for anti-fibrotic therapie

    Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

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    OBJECTIVE: We have recently shown a significant reduction in cytokine-induced transcription of type I collagen and fibronectin in systemic sclerosis (SSc) skin fibroblasts upon treatment with trichostatin A (TSA). Moreover, in a mouse model of fibrosis, TSA prevented the dermal accumulation of extracellular matrix. The purpose of this study was to analyze the silencing of histone deacetylase 7 (HDAC-7) as a possible mechanism by which TSA exerts its antifibrotic function. METHODS: Skin fibroblasts from patients with SSc were treated with TSA and/or transforming growth factor beta. Expression of HDACs 1-11, extracellular matrix proteins, connective tissue growth factor (CTGF), and intercellular adhesion molecule 1 (ICAM-1) was analyzed by real-time polymerase chain reaction, Western blotting, and the Sircol collagen assay. HDAC-7 was silenced using small interfering RNA. RESULTS: SSc fibroblasts did not show a specific pattern of expression of HDACs. TSA significantly inhibited the expression of HDAC-7, whereas HDAC-3 was up-regulated. Silencing of HDAC-7 decreased the constitutive and cytokine-induced production of type I and type III collagen, but not fibronectin, as TSA had done. Most interestingly, TSA induced the expression of CTGF and ICAM-1, while silencing of HDAC-7 had no effect on their expression. CONCLUSION: Silencing of HDAC-7 appears to be not only as effective as TSA, but also a more specific target for the treatment of SSc, because it does not up-regulate the expression of profibrotic molecules such as ICAM-1 and CTGF. This observation may lead to the development of more specific and less toxic targeted therapies for SSc

    Final State Interaction Effects in pol 3He(pol e,e'p)

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    Asymmetries in quasi-elastic pol 3He(pol e,e'p) have been measured at a momentum transfer of 0.67 (GeV/c)^2 and are compared to a calculation which takes into account relativistic kinematics in the final state and a relativistic one-body current operator. With an exact solution of the Faddeev equation for the 3He-ground state and an approximate treatment of final state interactions in the continuum good agreement is found with the experimental data.Comment: 11 pages, 6 figures, submitted to Phys. Lett. B, revised version, sensitivity study to relativity and NN-potential adde

    Nilpotent orbits and codimension-two defects of 6d N=(2,0) theories

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    We study the local properties of a class of codimension-2 defects of the 6d N=(2,0) theories of type J=A,D,E labeled by nilpotent orbits of a Lie algebra \mathfrak{g}, where \mathfrak{g} is determined by J and the outer-automorphism twist around the defect. This class is a natural generalisation of the defects of the 6d theory of type SU(N) labeled by a Young diagram with N boxes. For any of these defects, we determine its contribution to the dimension of the Higgs branch, to the Coulomb branch operators and their scaling dimensions, to the 4d central charges a and c, and to the flavour central charge k.Comment: 57 pages, LaTeX2
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