Targeting ATP12A, a non-gastric proton pump alpha subunit, for idiopathic pulmonary fibrosis treatment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE205849 | GEO | 2023/04/01
REPOSITORIES: GEO
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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: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.
2021-12-31 | GSE171532 | GEO
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
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
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
Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease causing alveolar remodeling, inflammation, and fibrosis. We utilized single cell RNA-sequencing (scRNA-Seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of epithelial cells from normal human lung defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified three distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and, an additional atypical "transitional" cell that contribute to pathological processes in IPF. Individual IPF cells frequently co-expressed alveolar AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-ß, HIPPO/YAP, P53, and AKT-PI3 Kinase. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. Single cell transcriptomic analyses of respiratory epithelial cells identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. Present scRNA-seq transcriptomic analysis of normal and IPF respiratory epithelial cells provides a rich data source to further explore lung health and disease.
2017-02-06 | GSE94555 | GEO
Project description:Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease causing alveolar remodeling, inflammation, and fibrosis. We utilized single cell RNA-sequencing (scRNA-Seq) to identify epithelial cell types and associated biological processes involved in the pathogenesis of IPF. Transcriptomic analysis of epithelial cells from normal human lung defined gene expression patterns associated with highly differentiated alveolar type 2 (AT2) cells, indicated by enrichment of RNAs critical for surfactant homeostasis. In contrast, scRNA-seq of IPF cells identified three distinct subsets of epithelial cell types with characteristics of conducting airway basal and goblet cells and, an additional atypical "transitional" cell that contribute to pathological processes in IPF. Individual IPF cells frequently co-expressed alveolar AT1, AT2, and conducting airway selective markers, demonstrating "indeterminate" states of differentiation not seen in normal lung development. Pathway analysis predicted aberrant activation of canonical signaling via TGF-ß, HIPPO/YAP, P53, and AKT-PI3 Kinase. Immunofluorescence confocal microscopy identified the disruption of alveolar structure and loss of the normal proximal-peripheral differentiation of pulmonary epithelial cells. Single cell transcriptomic analyses of respiratory epithelial cells identified loss of normal epithelial cell identities and unique contributions of epithelial cells to the pathogenesis of IPF. Present scRNA-seq transcriptomic analysis of normal and IPF respiratory epithelial cells provides a rich data source to further explore lung health and disease.
2016-12-08 | GSE86618 | GEO
Project description:A comprehensive understanding of the changes in gene expression in cell types involved in idiopathic pulmonary fibrosis (IPF) will shed light on the mechanisms underlying the loss of alveolar epithelial cells, and development of honeycomb cysts and fibroblastic foci. We sought to understand changes in IPF lung cell transcriptomes and gain insight into innate immune aspects of pathogenesis. We investigated IPF pathogenesis using single cell RNA-sequencing of fresh lung explants, comparing human IPF fibrotic lower lobes reflecting late disease, upper lobes reflecting early disease and normal lungs. IPF lower lobes showed increased fibroblasts, and basal, ciliated, goblet and club cells, but decreased alveolar epithelial cells, and marked alterations in inflammatory cells. We found three discrete macrophage subpopulations in normal and fibrotic lungs, one expressing monocyte markers, one highly expressing FABP4 and INHBA (FABP4hi), and one highly expressing SPP1 and MERTK (SPP1hi). SPP1hi macrophages in fibrotic lower lobes showed highly upregulated SPP1 and MERTK expression. Low-level local proliferation of SPP1hi macrophages in normal lungs was strikingly increased in IPF lungs. Co-localization and causal modeling supported the role for these highly proliferative SPP1hi macrophages in activation of IPF myofibroblasts in lung fibrosis. These data suggest SPP1hi macrophages contribute importantly to lung fibrosis in IPF, and that therapeutic strategies targeting MERTK and macrophage proliferation may show promise for treatment of this disease.
2019-06-21 | GSE128033 | GEO
Project description:Objective: Pulmonary complications in systemic sclerosis (SSc), including pulmonary fibrosis (PF) and pulmonary arterial hypertension (PAH), are the leading cause of mortality. We compared the molecular fingerprint of SSc lung tissues and matching primary lung fibroblasts to those of normal donors, and patients with idiopathic pulmonary fibrosis (IPF) and idiopathic pulmonary arterial hypertension (IPAH). Methods: Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively. Results: We identified a consensus of 242 and 335 genes that were differentially expressed in lungs and primary fibroblasts, respectively. Enriched function groups in SSc-PF and IPF lungs included fibrosis, insulin-like growth factor signaling and caveolin-mediated endocytosis. Functional groups shared by SSc-PAH and IPAH lungs included antigen presentation, chemokine activity, and IL-17 signaling. Conclusion: Using microarray analysis on carefully phenotyped SSc and comparator lung tissues, we demonstrated distinct molecular profiles in tissues and fibroblasts of patients with SSc-associated lung disease compared to idiopathic forms of lung disease. Unique molecular signatures were generated that are disease- (SSc) and phenotype- (PF vs PAH) specific. These signatures provide new insights into pathogenesis and potential therapeutic targets for SSc lung disease. Lung tissues were obtained from 33 patients with SSc who underwent lung transplantation. Tissues and cells from a subgroup of SSc patients with predominantly PF or PAH were compared to those from normal donors, patients with IPF, or IPAH. Microarray data was analyzed using Efficiency Analysis for determination of optimal data processing methods. Real time PCR and immunohistochemistry were used to confirm differential levels of mRNA and protein, respectively.
2013-06-21 | E-GEOD-48149 | biostudies-arrayexpress
Project description:The mast cell-specific metalloprotease CPA3 has been given important roles in lung tissue homeostasis and disease pathogenesis. However, the dynamics and spatial distribution of mast cells CPA3 expression in lung diseases remains unknown. Methods: Using a histology-based approach for spatial and quantitative simultaneous decoding of mRNA and protein expression at a single cell level, this study investigates the dynamics of CPA3 expression across mast cells residing in lungs from healthy controls and patients with severe chronic obstructive pulmonary disease (COPD) or idiopathic lung fibrosis (IPF). Results: Mast cells in COPD lungs had increased CPA3 mRNA (bronchioles p<0.001, pulmonary vessels p< 0.01, alveolar parenchyma p< 0.01) compared to controls, while granule stored CPA3 protein was unaltered. IPF lungs had a significant upregulation of both CPA3 mRNA (p<0.001) and protein (p<0.05) in the fibrotic alveolar tissue. IPF was also characterized by highest density of distal lung mast cells. As an indication of disease relevant increased CPA3 turnover, spatial expression maps revealed altered mast cell mRNA/protein quotients in lung areas subjected to disease-relevant histopathological alterations. Single cell RNA sequencing of bronchial mast cells confirmed CPA3 as a top expressed gene with potential links to both inflammatory and protective markers. Conclusion: This study shows that lung tissue mast cell populations in COPD and IPF-affected lungs have spatially complex and markedly up-regulated CPA3 expression profiles that correlates with sites of structural pathologies. Given the proposed roles of CPA3 in tissue homeostasis, remodeling and inflammation, these alterations are likely to have clinical consequences.
2022-07-28 | GSE201772 | GEO