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[Show abstract] [Hide abstract]
ABSTRACT: Renal fibrosis leads to end-stage renal dis-ease demanding renal replacement therapy because no adequate treatment exists. IFN-g is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically adminis-tered IFN-g causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell-specific delivery of IFN-g to platelet-derived growth factor receptor b (PDGFRb)-expressing myofibroblasts attenuates fibrosis in an obstructive ne-phropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-g conjugated to PDGFRb-recognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-g] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-g. PDGFRb expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with a-smooth muscle actin-positive (SMA +The FASEB Journal 12/2014; · 5.48 Impact Factor
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ABSTRACT: Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management.Scientific reports. 01/2015; 5:7916.
Dataset: Poosti The FASEB J 2014