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Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 (TGFβ1) siRNAs for Pulmonary Fibrosis

ABSTRACT: Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of TGFβ1 as the major player in the pathogenesis of the disease. This study designed novel human- and mouse-specific siRNAs and siRNA/DNA chimeras targeting both human and mouse common sequences and evaluated their inhibitory activity in pulmonary fibrosis induced by bleomycin and lung-specific transgenic expression of human TGFβ1. Selective novel sequences of siRNA and siRNA/DNA chimeras efficiently inhibited pulmonary fibrosis, indicating their applicability as tools for treating fibrotic disease in humans.

ORGANISM(S): Mus musculus

PROVIDER: GSE28122 | GEO | 2011/11/22

SECONDARY ACCESSION(S): PRJNA139843

REPOSITORIES: GEO

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Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 (TGFβ1) siRNAs for Pulmonary Fibrosis

Project description:Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of TGFβ1 as the major player in the pathogenesis of the disease. This study designed novel human- and mouse-specific siRNAs and siRNA/DNA chimeras targeting both human and mouse common sequences and evaluated their inhibitory activity in pulmonary fibrosis induced by bleomycin and lung-specific transgenic expression of human TGFβ1. Selective novel sequences of siRNA and siRNA/DNA chimeras efficiently inhibited pulmonary fibrosis, indicating their applicability as tools for treating fibrotic disease in humans. Total RNA was extracted from lung tissue from mice with bleomycin (BLM)-induced lung fibrosis treated with mouse TGFβ1 siRNAs or vehicle on different days after BLM infusion.

2011-11-22 | E-GEOD-28122 | biostudies-arrayexpress

GPCR-induced YAP activation sensitizes fibroblasts to profibrotic effects of TGFβ1

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Project description:To investigate TGFβ1 (a key member of the TGFβ superfamily) signaling in non-cancerous and cancerous cells derived from breast epithelium and what further response it might generate, we treated the cells with TGFβ1 or with conditioned media. We selected MCF10A non-tumorigenic breast epithelial cells (isolated from the mammary gland with fibrocystic disease) and MCF7 breast adenocarcinoma cells (estrogen receptor-positive, ER+). We followed a regimen of treating the cells for six consecutive days, with daily administration of TGFβ1 for two hours. The TGFβ1-containing medium was changed to a fresh one, which was collected after another 22 hours (so-called conditioned medium, CM) and administered to other cells. This enabled us to assess the ability of extracellularly secreted molecules to further induce a cellular response (bystander effect). RNA-seq analyses were performed on cells either directly treated with TGFβ1 in the above scheme or treated with a conditioned media for 1, 2, 3, 4, 5, or 6 days. The experiment was performed in three biological replicates, and each sample was sequenced separately. RNA-seg analysis in both cell lines allowed us to find the differences and similarities in response to TGFβ1 and CM. All 84 libraries were sequenced on Illumina NovaSeq6000 platform, in 2x150 mode, with a coverage of 60M reads/sample.

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TGFβ1 treatment of A2058 melanoma cells

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Transforming growth factor β1 (TGFβ1) and progesterone regulate matrix metalloproteinases (MMP) in human endometrial stromal cells.

Project description:ContextMenstruation is preceded by progesterone withdrawal and endometrial matrix remodeling predominantly through induction of matrix metalloproteinases (MMP) and recruitment of invading neutrophils.DesignUsing endometrial tissues from women during various phases of the menstrual cycle, we found that MMP2, MMP9, and MMP11 were up-regulated in the late secretory phase/premenstrual phase. Because TGFβ-responsive genes were also up-regulated in endometrium during this time, we tested the hypothesis that TGFβ1 and progesterone regulate expression of MMP in human endometrial stromal cells (HESC).ResultsTreatment of HESC with TGFβ1 resulted in marked increases in MMP2 and MMP11 mRNA and pro- and active MMP2 activity. Progesterone inhibited TGFβ1-induced stimulation of MMP2 and MMP11 through its nuclear hormone receptors. Interestingly, TGFβ1 also decreased progesterone receptor (PR)-A and PR-B in HESC with a more pronounced effect on PR-A.ConclusionsThese data support the hypothesis that TGFβ1 has endogenous anti-progestational effects in HESC and that the opposing effects of progesterone and TGFβ1 are important in regulation of matrix integrity in human endometrium.

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Fibrosis growth factor 23 is a promoting factor for cardiac fibrosis in the presence of transforming growth factor-β1

Project description:We demonstrated that, four weeks after the pulmonary artery banding (PAB) operation, rats could be divided into two groups: an F+ group in which the fibrotic area occupied more than 6.5% of the whole area of the heart tissues, and an F- group in which the fibrotic area occupied less than 6.5% of this area. We used microarrays to elucidate the fibrosis initiating master factor using heart samples obtained from PAB or sham-operated rats.

2019-12-10 | GSE141650 | GEO

SSc biomarkers detection in the secretome of TGF1-activated primary human lung fibroblasts.

Project description:TGFβ1 is a profibrotic mediator that contributes to a broad spectrum of pathologies, including pulmonary fibrosis (PF). However, the secretome of TGFβ1-stimulated primary human normal lung (NL) fibroblasts has not been well characterized. Using fluorescent 2-dimensional gel electrophoresis (2D-PAGE) and differential gel electrophoresis (DIGE), we identified 37 differentially secreted proteins in the conditioned media of TGFβ1-activated NL fibroblasts and generated a protein-protein association network of the TGFβ1 secretome using STRING. Functional enrichment revealed that biological processes and pathways characteristics of PF were enriched. Using the DrugBank database, we determined that 32 of the secreted proteins are targets of known experimental, investigational and approved drugs. Additionally, by comparing the TGFβ1 secretome of NL fibroblasts to proteomic biomarkers from biological fluids of systemic sclerosis (SSc) patients, we identified 11 overlapping proteins. Together our data validate the TGFβ1-induced secretome of NL fibroblasts as a valid in vitro model that reflects SSc biomarkers and identifies potential therapeutic targets for SSc-PF.

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Molecular characterization of a precision-cut rat lung slice model for the evaluation of anti-fibrotic drugs

Project description:The translation of novel pulmonary fibrosis therapies from preclinical models into the clinic represents a major challenge demonstrated by the high attrition rate of compounds that showed efficacy in preclinical models but demonstrated no significant beneficial effects in clinical trials. Precision-cut lung tissue slice (PCLS) contains all major cell types of the lung and preserves the original cell-cell and cell-matrix contacts. It represents a promising ex vivo model to study pulmonary fibrosis. In this study, using RNA sequencing, we demonstrated that TGFβ1 induced robust fibrotic responses in the rat PCLS model as it changed the expression of genes functionally related to extracellular matrix remodeling, cell adhesion, epithelial-to-mesenchymal transition and various immune responses. Nintedanib, pirfenidone and sorafenib each reversed a subset of genes modulated by TGFβ1 and of those genes we identified 229 genes whose expression was reversed by all three drugs. These genes define a molecular signature characterizing many aspects of pulmonary fibrosis pathology and its attenuation in the rat PCLS fibrosis model. A panel of 12 genes and 3 secreted biomarkers including procollagen I, HA and WISP1 were validated as efficacy endpoints for the evaluation of anti-fibrotic activity of experimental compounds. Finally, we showed that blockade of αV integrins suppressed TGFβ1-induced fibrotic responses in the rat PCLS fibrosis model. Overall, our results suggest that the TGFβ1-induced rat PCLS fibrosis model may represent a valuable system for target validation and to determine the efficacy of experimental compounds.

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