MTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis
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PROVIDER: PRJNA1129140 | ENA |
REPOSITORIES: ENA
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Project description:Pulmonary fibrosis (PF) is associated with many chronic lung diseases including Systemic sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF) and Cystic Fibrosis (CF) which are characterized by the progressive accumulation of stromal cells and formation of scar tissue. Pulmonary fibrosis is a dysregulated response to alveolar injury which causes a progressive decline in lung function and refractory to current pharmacological therapies. Airway and alveolar epithelial cells and stromal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Recent animals models generated in our lab demonstrate clinical phenotypes seen in human fibrotic disease. The mouse model of transforming growth factor-? (TGF?)-induced fibrosis include conditionally expressing TGF? in the lung epithelium under control of the CCSP promoter driving rtTA expression (CCSP/TGF?). This allow the TGF? is only expressed in airway and alveolar epithelial cells and only when mice fed doxycycline (Dox). Similar to PF in humans, TGF? mice on Dox developed a progressive and extensive adventitial, interstitial and pleural fibrosis with a decline in lung mechanics. Thus, the TGF? transgenic mouse is a powerful model to determine lung cell-specific molecular signatures involved in pulmonary fibrosis. In this study, we sought to determine changes in the transcriptome during TGF?-induced pulmonary fibrosis. Our results showed that several pro-fibrotic genes increased in the lungs of TGF? mice. This study demonstrates that WT1 network gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a critical regulator fibrotic lung disease. mRNA profiles of CCSP/- and CCSP/TGFalpha mice treated with Dox
2015-03-07 | E-GEOD-66634 | biostudies-arrayexpress
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
2019-09-17 | GSE124780 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to see whether the cross-talk between transforming growth factor-b (TGF-b), a central mediator in the pathogenesis of pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether taking advantage of the cross-talk between TGF-b and periostin, inhibitors for integrin aVb3, a periostin receptor, can block pulmonary fibrosis in the model mice. We found that there exists a cross-talk between TGF-b and periostin signals via aVb3/b5 converging into Smad3. This cross-talk is important for expression of several downstream molecules of TGF-b including serpin family E member 1, CCN family member 2/connective tissue growth factor, insulin-like growth factor binding protein-3, and IL-11, all of which have been already shown to be important for pulmonary fibrosis. We, moreover, found several potent integrin inhibitors to block the cross-talking with TGF-b signals and CP4715, one of the compounds, improved bleomycin-induced pulmonary fibrosis in mice. These results suggest that the cross-talk between TGF-b and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block the cross-talk between TGF-b and periostin.
2019-09-17 | GSE124781 | GEO
Project description:We investigated the effects of mTOR and ATF4 on gene expression in human lung fibroblasts using RNA-sequencing. We found both ATF4 and mTOR regulate expression of genes that are involved in controlling amino acid synthesis and transportation. mTOR additionally regulates genes that are involved in glycolysis and oxidative phosphorylation.
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Project description:The response to a 4 hour treatment with TGFbeta (4 ng/ml) was evaluated in lung fibroblasts derived from three controls (normal periphery of resected tumor), open lung biopsies from three patients with idiopathic pulmonary fibrosis (usual interstitial pneumonia pattern on biopsy) and from three patients with fibrosing alveolitis associated with systemic sclerosis (fibrotic non specific interstitial pneumonia pattern on biopsy). Lung fibroblasts were grown to confluence in DMEM with 10% fetal calf serum. At confluence, lung fibroblasts were serum-deprived overnight, and exposed to either 4 ng/ml of activated TGF-Ã1 (R&D Systems) or serum-free culture medium with 0.1% BSA for four hours.
2007-08-04 | E-GEOD-1724 | biostudies-arrayexpress
Project description:Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGF? in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGF? mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative gene changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role. mRNA profiles of CCSP/TGFalpha mice treated with vehicle, ARRY, PX-866, ARRY/PX-866
2013-12-03 | E-GEOD-52854 | biostudies-arrayexpress
Project description:A hallmark of pulmonary fibrosis is aberrant activation of lung fibroblasts into pathological fibroblasts producing excessive extracellular matrix (ECM). Thus, identification of key regulator(s) driving the generation of pathological fibroblasts can inform effective countermeasures against disease progression. In this study, we show that Leptin Receptor (Lepr)+ fibroblasts arising during alveologenesis include Signal Peptide-CUB-EGF Domain-containing Protein 2 (Scube2)+ alveolar fibroblasts as a major constituent significantly contributing to collagen triple helix repeat containing 1 (Cthrc1)+ Periostin (Postn)+ pathological fibroblasts in two mouse models of pulmonary fibrosis. Genetic ablation of the Postn+ pathological fibroblasts attenuates fibrosis. Comprehensive analysis of single cell RNA sequencing (scRNA-seq) and single cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) reveal Runt related transcription factor 2 (RUNX2) as a key regulator of fibrotic genes. Consistently, conditional deletion of Runx2 with Lepr-CreERT2 or Scube2-CreERT2 reduces the generation of pathological fibroblasts, ECM deposition, and pulmonary fibrosis. Therefore, Lepr+ derived fibroblasts which include Scube2+ alveolar fibroblasts are a key source of pathological fibroblasts, and targeting Runx2 provides a potential treatment option for pulmonary fibrosis.
2024-11-25 | GSE278419 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF)
| PRJNA802122 | ENA
Project description:Pulmonary fibrosis (PF) is a terminal lung disease characterized by fibroblast proliferation, accumulation of extracellular matrix accumulation, inflammatory damage, and tissue structure destruction. The pathogenesis of this disease, especiallyparticularly idiopathic pulmonary fibrosis (IPF), is still remains unknown. Macrophages play a significant rolemajor roles in organ fibrosis diseases, including pulmonary fibrosis. The phenotype and polarization of macrophages are closely associated with the process of pulmonary fibrosis. A new direction in drug research on for antipulmonary fibrosis is focuseds on developing drugs that maintain the stability of the pulmonary microenvironment. Here, tThrough bioinformatics analysis and experiments involving bleomycininduced pulmonary fibrosis in mice, we confirmed the importance of macrophage polarization in IPF. The analysis revealed that macrophage polarization in IPF involves a change in the phenotypice spectrum. Furthermore, the experiments demonstrated showed high expression of M2-type macrophage-related-associated biomarkers and inducible nitric oxide synthase, thus indicating an imbalance in M1/M2 polarization of pulmonary macrophages in mice with pulmonary fibrosis. Our investigation revealed that the ethyl acetate extract (HG2) obtained from the roots of Prismatomeris connataPrismatomeris connata Y. Z. Ruan exhibits therapeutic efficacy against bleomycin-induced pulmonary fibrosis. HG2 demonstrates the ability to modulates macrophage polarization, alterations in the TGF‐β/Smads pSmad pathway, and downstream protein expression in the context of pulmonary fibrosis. Drawing upon On the basis of our findings, we believe that HG2 exhibits has potential as a novel component of traditional Chinese medicine component for treating pulmonary fibrosis.
2024-01-07 | PXD048007 | Pride
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal form of interstitial lung disease associated with progressive scarring of lung tissue and declining pulmonary function in aging individuals. Here we employ data mining and single cell RNA sequencing (scRNAseq) to define candidate drivers of AT2 senescence in IPF lung tissue. We show that AT2 cells isolated from IPF lung tissue exhibit characteristic features of cellular senescence and reduced abundance of Sin3a, critical determinant of endodermal progenitor cell maintenance in the developing lung. Conditional loss of Sin3a within AT2 cells of the adult mouse lung activated a program of p53-dependent cellular senescence and AT2 cell depletion, leading to progressive pulmonary fibrosis. In contrast, ablation of AT2 cells through conditional activation of a DTA toxin gene led to transient fibrosis that resolved over time, suggesting that senescence of AT2 cells was a critical driver of progressive fibrosis. Activation of b6 integrin was observed within a subset of AT2 cells with Sin3a loss-of-function that localized to the advancing margin of advancing fibroproliferative lesions. Systemic inhibition of TGF signaling or delivery of senolytic drugs prevented lung fibrosis in Sin3a loss-of-function mice. Our findings establish a novel mouse model that recapitulates key pathological features of human IPA and show that p53-dependent senescence is a proximal regulator of TGF induction and progressive pulmonary fibrosis.
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