Maladaptive TGF-β Signals to the Alveolar Epithelium Drive Fibrosis after COVID-19 Infection
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ABSTRACT:
PROVIDER: PRJNA933176 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23384980.fastq.gz | Fastqsanger.gz | |||
| SRR23384981.fastq.gz | Fastqsanger.gz | |||
| SRR23384982.fastq.gz | Fastqsanger.gz | |||
| SRR23384983.fastq.gz | Fastqsanger.gz | |||
| SRR23384984.fastq.gz | Fastqsanger.gz |
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Project description:TGF-beta treated airway epithelium
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Project description:Alveolar type II (ATII) epithelial cells function as stem cells, contributing to alveolar renewal, repair and cancer. Therefore, they are a highly relevant model for studying lung diseases, including acute injury, fibrosis and cancer, in which signals transduced by RAS and transforming growth factor (TGF)-ß play critical roles. To identify downstream molecular events following RAS and/or TGF-ß activation, we performed proteomic analysis using a quantitative label-free approach (LC-HDMSE) to provide in-depth proteome coverage and estimates of protein concentration in absolute amounts. Contact: pjss@soton.ac.uk
2021-02-04 | PXD023720 | Pride
Project description:We have performed single cell RNA sequencing on explant tissue of post-acute sequelae SARS-CoV-2 infection (PASC) patients. The study focused on epithelial cells (Epcam+) and immune cells (CD45+) cells. We further compared our PASC sample with Donor and IPF samples from GSE146981 and GSE135893.
2023-05-15 | GSE224955 | GEO
Project description:Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-β1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with ∼16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-β1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a novel HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-β1 signaling in pulmonary disease.
2025-06-23 | GSE269634 | GEO
Project description:Disparate Oxidant-related Gene Expression of Human Small Airway Epithelium Compared to Autologous Alveolar Macrophages in Response to the In Vivo Oxidant Stress of Cigarette Smoking The oxidant burden of cigarette smoking induces lung cell dysfunction, and play a significant role in the pathogenesis of lung disease. Two cell populations directly exposed to the oxidants in cigarette smoke are the small airway epithelium and alveolar macrophages. Of these, the epithelium appears to be more vulnerable to smoking, becoming disordered in differentiation, repair and function, while alveolar macrophages become activated, without becoming diseased. In this context, we asked: for the same individuals, what is the baseline trancriptome of oxidant-related genes in small airway epithelium compared to alveolar macrophages and do the responses of the transcriptome of these 2 cell populations differ substantially to inhaled cigarette smoke? To address these questions we used microarray gene expression and TaqMan analysis to assess the gene expression profile of known oxidant-related genes in paired samples recovered by bronchoscopy from small airway epithelium and alveolar macrophages from the same healthy nonsmokers and normal smokers. Of the 155 oxidant-related genes surveyed, 122 (77%) were expressed in both cell populations in nonsmokers. However, of the genes expressed by both cell populations, oxidant related gene expression levels were higher in alveolar macrophages (67 genes, 43%) than small airway epithelium (37 genes, 24%). There were more oxidant-related genes uniquely expressed in the small airway epithelium (17%), than in alveolar macrophages (5%). In healthy smokers, the majority of oxidant-related genes were expressed in both cell populations, but there were marked differences in the numbers of oxidant-related genes that smoking up- or down-regulated. While smoking up-regulated 15 genes (10%) and down-regulated 7 genes (5%) in the small airway epithelium, smoking had far less effect on alveolar macrophages [only 4 (3%) genes up-regulated, and only 1 (0.6%) down-regulated]. Only a small number of smoking responsive oxidant-related genes overlapped between the two cell types (2 up-regulated, and no down-regulated genes). Consistent with this observation, pathway analysis of smoking-responsive genes in the small airway epithelium showed oxidant-related pathways dominated, but in alveolar macrophages immune-response pathways dominated. Thus, the responses of the oxidant-related transcriptome of cells with an identical genome and exposed to the same oxidant stress of cigarette smoking are very different, with responses of oxidant-related genes of alveolar macrophages far more subdued than that of small airway epithelium, consistent with the clinical observation that, while the small airway epithelium is vulnerable, alveolar macrophages are not "diseased" in response to the oxidant stress of cigarette smoking. Gene expression profiles of known oxidant-related genes in paired samples recovered by bronchoscopy from small airway epithelium and alveolar macrophages from the same healthy nonsmokers and normal smokers.
2011-09-11 | E-GEOD-13931 | biostudies-arrayexpress
Project description:A mathematical ODE based model of the innate immune response to SARS-CoV-2 in the alveolar epithelium.
2021-11-17 | MODEL2111170001 | BioModels
Project description:SARS-CoV-2 seriously injures human alveoli and causes severe respiratory illness. Histopathologic evidences suggested alveolar-capillary barrier integrity is compromised in COVID-19 deaths, however, little is known about how it is disrupted. In this study, we investigated the effects of SARS-CoV-2 infection on alveolar epithelium and pulmonary microvascular endothelium, and tried to elucidate the cross-talk between them during viral infection. Under monoculture system, SARS-CoV-2 infection caused massive virus replication and dramatic organelles re-modeling in alveolar epithelial cells. While, as for pulmonary microvascular endothelial cells, direct viral exposure had little effect on them, but treatment with culture supernatant from infected epithelial cells significantly damaged them, which suggested SARS-CoV-2 affected endothelium indirectly, possibly by substances released from infected alveolar epithelium. Then, we tested SARS-CoV-2 infection in an alveolar epithelium/endothelium co-culture system, and found viral infection caused global proteomic modulations and ultrastructural changes in both cell types. Especially for alveolar epithelial cells, viral infection elicited significant protein changes and structural reorganizations across many sub-cellular compartments. Among the affected organelles, mitochondrion seems to be a primary target organelle. In addition, based on proteomic analysis and EM clues, we tested several autophagy inhibitors, and discovered one of them, Daurisoline, could inhibit virus replication effectively in cells. Collectively, our study revealed the distinctive responses of alveolar epithelium and microvascular endothelium to SARS-CoV-2 infection, which will expand our understanding of COVID-19 and helpful for targeted drug development.
2021-11-11 | PXD029653 | Pride
Project description:SARS-CoV-2 seriously injures human alveoli and causes severe respiratory illness. Histopathologic evidences suggested alveolar-capillary barrier integrity is compromised in COVID-19 deaths, however, little is known about how it is disrupted. In this study, we investigated the effects of SARS-CoV-2 infection on alveolar epithelium and pulmonary microvascular endothelium, and tried to elucidate the cross-talk between them during viral infection. Under monoculture system, SARS-CoV-2 infection caused massive virus replication and dramatic organelles re-modeling in alveolar epithelial cells. While, as for pulmonary microvascular endothelial cells, direct viral exposure had little effect on them, but treatment with culture supernatant from infected epithelial cellls significantly damaged them, which suggested SARS-CoV-2 affected endothelium indirectly, possibly by substances released from infected alveolar epithelium. Then, we tested SARS-CoV-2 infection in an alveolar epithelium/endothelium co-culture system, and found viral infection caused global proteomic modulations and ultrastructual changes in both cell types. Especially for alveolar epithelial cells, viral infection elicited significant protein changes and structural reorganizations across many sub-cellular compartments. Among the affected organelles, mitochondrion seems to be a primary target organelle. In addition, based on proteomic analysis and EM clues, we tested several autophagy inhibitors, and discovered one of them, Daurisoline, could inhibit virus replication effectively in cells. Collectively, our study revealed the distinctive responses of alveolar epithelium and microvascular endothelium to SARS-CoV-2 infection, which will expand our understanding of COVID-19 and helpful for targeted drug development.
2020-12-04 | PXD020470 | Pride
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