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Alteration in the transcriptome of lung resident fibroblast isolated from fibrotic lungs of IPF upon genetic knockdown of SOX9

ABSTRACT: 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 mesenchymal 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 mesenchymal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Our new findings have identified the aberrant activation of Sox9 in lung resident fibroblasts and myofibroblasts in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin-induced pulmonary fibrosis. In this study, we sought to determine Sox9-driven gene networks in lung resident fibroblast during pulmonary fibrosis. Our results showed that Sox9 regulates the transcriptional changes that are required for the fibroblast activation including migration, myofibroblast transformation, survival and extracellular matrix deposition during pulmonary fibrosis. In summary, this new study demonstrates that Sox9 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171532 | GEO | 2021/12/31

REPOSITORIES: GEO

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Alteration in the transcriptome of lung resident fibroblast upon genetic knockdown of Wilms' tumor1 transcription factor

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 published reports from our lab demonstrated the aberrant activation of Wilms' tumor1 (WT1) transcription factor in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of WT1 in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that WT1 regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast transformation and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that WT1 is a critical regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention.

2018-08-01 | GSE110177 | GEO

Alteration in the transcriptome of lung resident fibroblast isolated from fibrotic lungs of TGFalpha mice upon genetic knockdown of Aurora Kinase B

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 mesenchymal 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 mesenchymal cells contribute to pulmonary fibrosis but the cell-specific pathways and gene networks that are responsible for the pathophysiology are unknown. Our new findings have identified the abberent activation of Aurora Kinase B (AURKB) in lung resident fibroblast and myofibroblast in IPF lung biopsies and the mouse model of transforming growth factor-α (TGFα) and bleomycin induced fibrosis. In this study, we sought to determine the role of AURKB in transcriptome changes in lung resident fibroblast during pulmonary fibrosis. Our results showed that AURKB regulates the transcriptional changes that are required for the fibroblast activation processes such fibroproliferation, myofibroblast survival and extracellular matrix deposition during pulmonary fibrosis. Finally, this study demonstrates that AURKB is a critcal regulator of fibroblast activation in IPF and hence serve as a target for therapeutic intervention. Grantee: Satish K Madala Grantor: US Department of Defense funds Grant ID: W81XWH-17-1-0666 Grant Title: Therapeutic Benefit of Hsp90 Inhibition in Pulmonary Fibrosis

2020-07-08 | GSE153898 | GEO

Redundant effects of Pirfenidone against fibroblast activation and severe fibrotic lung disease

Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFα is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFα alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFα-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFα model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFα mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFα-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts.

2022-06-01 | GSE199034 | GEO

Alteration in the transcriptome of the lung during TGFα-induced pulmonary fibrosis

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-α (TGFα)-induced fibrosis include conditionally expressing TGFα in the lung epithelium under control of the CCSP promoter driving rtTA expression (CCSP/TGFα). This allow the TGFα is only expressed in airway and alveolar epithelial cells and only when mice fed doxycycline (Dox). Similar to PF in humans, TGFα mice on Dox developed a progressive and extensive adventitial, interstitial and pleural fibrosis with a decline in lung mechanics. Thus, the TGFα 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 TGFα-induced pulmonary fibrosis. Our results showed that several pro-fibrotic genes increased in the lungs of TGFα 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.

2015-03-07 | GSE66634 | GEO

Transcription profiling of human myofibroblasts isolated from patients with idiopathic pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF), a chronic progressive lung disease of unknown etiology, is characterized by the expansion of myofibroblasts and abnormal deposition of extracellular matrix in the lung parenchyma. To elucidate the molecular mechanisms that lead to IPF, we analyzed myofibroblasts established from patients with IPF by oligonucleotide microarrays. Gene expression profiles revealed a novel pathophysiologic function of myofibroblasts as a generator of reactive oxygen species, and a self-defense mechanism against oxidative stress of their own generating. Experiment Overall Design: We isolated two myofibroblast cell culture from patients with idiopathic pulmonary fibrosis. Embryonic pulmonary fibroblast was used for the reference.

2008-06-15 | E-GEOD-6804 | biostudies-arrayexpress

LKB1 inhibition in alveolar epithelial cells induces fibroblast activation in pulmonary fibrosis [RNA-seq in 2D-cultured ATII]

Project description:Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and lethal lung disease. The initiation of IPF involves microinjuries to and/or dysfunction of the alveolar epithelium, but factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells induces autophagy inhibition and EMT as a consequence. In IPF lungs, this is caused by a downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and lung fibroblast MRC5 coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.

2023-08-09 | GSE205969 | GEO

LKB1 inhibition in alveolar epithelial cells induces fibroblast activation in pulmonary fibrosis [RNA-seq in 3D co-cultured ATII+MRC5]

2023-08-09 | GSE205965 | GEO

Alteration in the transcriptome of the lung during TGF?-induced pulmonary fibrosis

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

Bi-directional epithelial-mesenchymal crosstalk provides self-sustaining pro-fibrotic signals in pulmonary fibrosis

Project description:Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2-4 years. Injury to and/or dysfunction of alveolar epithelium are strongly implicated in IPF disease initiation, but what factors determine why fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that ZEB1-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments TGF-β-induced profibrogenic responses in underlying lung fibroblasts by paracrine signalling. Here we investigated bi-directional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA sequencing (RNA-seq) of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced EMT identified many differentially expressed genes including those involved in cell migration and extracellular matrix (ECM) regulation. We confirmed that paracrine signalling between AS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a ZEB1-tissue plasminogen activator (tPA) axis. In a reciprocal fashion, paracrine signalling from TGF-β-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially via the secreted protein, SPARC. Together these data identify that aberrant bi-directional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining pro-fibrotic signals.

2021-08-19 | PXD025821 | Pride

Spatial transcriptome profiling identifies CREB1 as a regulator of core transcriptional programs in idiopathic pulmonary fibrosis

Project description:A defining feature of idiopathic pulmonary fibrosis is the regional heterogeneity of the lung pathology. Here we established methodology to study the transcriptome of spatially discrete morphological areas in IPF lung tissue through the integration of laser capture microdissection of formalin fixed paraffin embedded lung tissue with low input RNA-Seq. We applied this methodology to obtain an in situ transcriptome for fibroblast foci and alveolar septae from IPF tissue as well as alveolar septae from age sex-matched control lung tissue. Differential gene expression analysis was performed between IPF alveolar septae vs control alveolar septae and between IPF fibroblast foci vs alveolar epithelium. Metacore TM was used for gene enrichment analysis of significantly differentially expressed genes, for transcription factor (TF) network analysis to identify predicted TF from human TF-target gene interaction.

2022-03-02 | GSE169500 | GEO

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