Therapy for Fibrotic Diseases: Nearing the Starting Line
ABSTRACT Fibrosis, or the accumulation of extracellular matrix molecules that make up scar tissue, is a common feature of chronic tissue injury. Pulmonary fibrosis, renal fibrosis, and hepatic cirrhosis are among the more common fibrotic diseases, which in aggregate represent a huge unmet clinical need. New appreciation of the common features of fibrosis that are conserved among tissues has led to a clearer understanding of how epithelial injury provokes dysregulation of cell differentiation, signaling, and protein secretion. At the same time, discovery of tissue-specific features of fibrogenesis, combined with insights about genetic regulation of fibrosis, has laid the groundwork for biomarker discovery and validation, and the rational identification of mechanism-based antifibrotic drugs. Together, these advances herald an era of sustained focus on translating the biology of fibrosis into meaningful improvements in quality and length of life in patients with chronic fibrosing diseases.
- SourceAvailable from: Saleh Yazdani
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- "The direct link between inflammation and fibrosis has been well established as well (Wick et al., 2013). Despite many clinical and experimental investigations, effective treatment for fibrosis is still lacking in the clinic (Friedman et al., 2013). FTY720, an S1P analog, effectively inhibits the egress of T and B cells from lymph nodes (Kabashima et al., 2006; Matloubian et al., 2004), thereby reducing the number of antigen-primed/restimulated cells that recirculate to peripheral inflammatory tissues (Brinkmann and Lynch, 2002), and consequently halts inflammation. "
ABSTRACT: Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric interventions are not always successful, and residual proteinuria often leads to renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. We previously showed that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these interstitial events in proteinuria is not clear yet. To this end, we specifically blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte/macrophage influx (clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist FTY720) separately to investigate the role and the possible interaction of each of these phenomena in tubulointerstitial remodeling in proteinuric nephropathy. Proteinuria was induced in three-month old male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria has developed, rats were treated for another 6 weeks by anti-VEGFR3 antibody, clodronate liposomes, and FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of macrophages, T cells and myofibroblasts, and collagen III deposition and interstitial fibrosis significantly increased at week 12 vs. week 6. Anti-VEGFR3 antibody prevented lymphangiogenesis in proteinuric rats, however without significant effects on inflammatory and fibrotic markers, and proteinuria. Clodronate liposomes inhibited macrophage influx, partly reduced myofibroblast expression; however, neither significantly prevented the development of lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented myofibroblast accumulation and T cell influx and interstitial fibrosis, partially declined macrophage number and proteinuria; however, it did not influence significantly on lymphangiogenesis and collagen III deposition. This study showed that proteinuria-induced interstitial fibrosis cannot be halted by blocking lymphangiogenesis or influx of macrophages. On the other hand, FTY720 treatment could prevent T-cells influx, myofibroblasts accumulation and interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We conclude that tubulointerstitial fibrosis and inflammation are separate from lymphangiogenesis, at least under proteinuric conditions. © 2015. Published by The Company of Biologists Ltd.Disease Models and Mechanisms 05/2015; DOI:10.1242/dmm.018580 · 5.54 Impact Factor
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- "The example of TGF-β1 hyper-activity in Marfan syndrome demonstrates that inhibition of LTBP binding to the ECM will need to be investigated with care as one possible strategy to prevent TGF-β1 activation in fibrosis. One the ECM side, current strategies aim at generally reducing the crosslink-degree which contributes to both, scar stiffening and binding of LTBP-1; targets are transglutaminases, lysyl oxidases, lysyl oxidase-like enzymes, and lysyl hydroxylases (reviewed in   ). Proteoglycans, in particular heparin/heparan sulfate are other attractive targets in the ECM due to their mediating role between different fibrillar ECM proteins as well as LTBPs   . "
ABSTRACT: Physiological tissue repair aims at restoring the mechano-protective properties of the extracellular matrix. Consequently, redundant regulatory mechanisms are in place ensuring that tissue remodelling terminates once matrix homeostasis is re-established. If these mechanisms fail, stromal cells become continuously activated, accumulate excessive amounts of stiff matrix, and fibrosis develops. In this mini-review, I develop the hypothesis that the mechanical state of the extracellular matrix and the pro-fibrotic transforming growth factor (TGF)-β1 cooperate to regulate the remodelling activities of stromal cells. TGF-β1 is stored in the matrix as part of a large latent complex and can be activated by cell contractile force that is transmitted by integrins. Matrix straining and stiffening lower the threshold for TGF-β1 activation by increasing the mechanical resistance to cell pulling. Different elements of this mechanism can be pharmacologically targeted to interrupt the mechanical positive feedback loop of fibrosis, including specific integrins and matrix protein interactions. Copyright © 2015. Published by Elsevier B.V.Matrix biology: journal of the International Society for Matrix Biology 05/2015; 8. DOI:10.1016/j.matbio.2015.05.006 · 3.65 Impact Factor
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- "Current treatments of tissue fibrosis mostly rely on targeting the inflammatory response; however, these are ultimately ineffective in preventing progression of the disease, underscoring the need for new mechanistic insights and therapeutic approaches (Friedman et al, 2013). Recent studies indicate the involvement of miRNAs in pulmonary fibrosis (Pandit et al, 2011). "
ABSTRACT: Over the last decade, great enthusiasm has evolved for microRNA (miRNA) therapeutics. Part of the excitement stems from the fact that a miRNA often regulates numerous related mRNAs. As such, modulation of a single miRNA allows for parallel regulation of multiple genes involved in a particular disease. While many studies have shown therapeutic efficacy using miRNA inhibitors, efforts to restore or increase the function of a miRNA have been lagging behind. The miR-29 family has gained a lot of attention for its clear function in tissue fibrosis. This fibroblast-enriched miRNA family is downregulated in fibrotic diseases which induces a coordinate increase of many extracellular matrix genes. Here, we show that intravenous injection of synthetic RNA duplexes can increase miR-29 levels in vivo for several days. Moreover, therapeutic delivery of these miR-29 mimics during bleomycin-induced pulmonary fibrosis restores endogenous miR-29 function whereby decreasing collagen expression and blocking and reversing pulmonary fibrosis. Our data support the feasibility of using miRNA mimics to therapeutically increase miRNAs and indicate miR-29 to be a potent therapeutic miRNA for treating pulmonary fibrosis.EMBO Molecular Medicine 09/2014; 6(10). DOI:10.15252/emmm.201303604 · 8.25 Impact Factor