Ontology highlight
ABSTRACT:
PROVIDER: PRJEB22172 | ENA |
REPOSITORIES: ENA
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Project description:A muco-inflammatory milieu characterizes early cf lung disease
| PRJEB22216 | ENA
Project description:Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
2021-09-10 | GSE154807 | GEO
Project description:Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
2021-09-10 | GSE154804 | GEO
Project description:SARS-CoV-2 (SCV2) infection leads to diverse clinical outcomes ranging from asymptomatic to fatal disease. Co-morbidities, age and host genetics together with immune status affect disease severity. However, the range of innate inflammatory pathways critical for limiting early viral replication and whether the inflammatory history and milieu of the lung microenvironment at the time of exposure impacts early control of SCV2 infection remain largely unexplored. Here, we investigated the roel of prior TLR stimualtion on early viral rpelciation in the lungs of K18 mice
2024-04-17 | GSE254993 | GEO
Project description:Cystic fibrosis (CF) is an inherited, multi-system disease caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a ubiquitous ion channel important for epithelial hydration. A direct consequence of this dysfunction is impaired mucociliary clearance, chronic airway infection and a persistent neutrophilic inflammatory response that results in progressive loss of lung function, development of respiratory failure and premature death. Partial restoration of CFTR function is now possible for most CF patients through mutation specific CFTR modulators. Ivacaftor monotherapy produces significant clinical improvement in CF patients with the G511D mutation. Dual therapy, combining ivacaftor with lumacaftor or tezacaftor, results in modest clinical improvements in patients homozygous for F508del. More recently, triple therapy with elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic improvements in lung function and quality of life in patients homozygous and heterozygous for F508del. Sputum proteomics is a powerful research technique capable of identifying important airway disease mechanisms by interrogating the proteome, an entire set of proteins within biological samples. It has confirmed the central role of neutrophilic immune dysregulation in CF and non-CF bronchiectasis, particularly involving the release of antimicrobial proteins and neutrophil-extracellular traps (NETs), and through impaired anti-inflammatory mechanisms. These processes produce distinct molecular signatures within the sputum proteome that become increasingly abnormal with chronic airway infection and progressive lung disease severity. In CF patients, airway and systemic inflammatory cytokines potentially related to these signatures reduce with the various forms of CFTR modulation. To date, no studies of ETI therapy in CF lung disease have assessed large-scale change in protein expression using untargeted proteomics. We hypothesised that ETI therapy would shift the sputum proteome toward health, potentially normalising airway biology in people with CF. The objectives of this study were to investigate changes in the CF sputum proteome with the introduction of ETI, correlate these with changes in clinical markers of disease severity, and make comparisons with the sputum proteome in healthy controls and in repeat samples from CF patients not suitable for ETI therapy. We also explored which molecular pathways associated with CF lung disease did not change with ETI.
2023-11-14 | PXD041950 | Pride
Project description:Macrophage plasticity allows cells to adopt different phenotypes, a property with potentially important implications in chronic pulmonary disorders such as cystic fibrosis (CF). We examined the transcriptional and functional significance of macrophage repolarization from an “M1” (LPS-stimulated) towards an “M2” phenotype using 5 stimuli. We found that macrophages exhibit highly diverse responses to distinct M2-polarizing stimuli. Specifically, we observed that IL-10 abrogated LPS-tolerance allowing for rapid restoration of LPS responsiveness. In contrast, IL-4 enhanced LPS-tolerance, dampening pro-inflammatory responses after repeat LPS challenge. We found enrichment of phagocytosis-associated pathways in macrophages stimulated with IL-10, leading them to display the greatest efferocytosis ability. Finally, we observed that CF macrophages had intact reparative responses, suggesting that macrophage contributions to CF lung disease are shaped by their environmental milieu and are modifiable. These findings highlight the diversity of macrophage activation states, attribute functional consequences to these stimuli, and provide a unique resource of human macrophage repolarization markers.
2018-09-30 | GSE100521 | GEO
Project description:Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
2021-09-10 | GSE154803 | GEO
Project description:Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
2021-09-10 | GSE154805 | GEO
Project description:Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
2021-09-10 | GSE154806 | GEO
Project description:Progressive lung disease remains the major cause of morbidity and mortality of people with cystic fibrosis (CF). CF lung disease evolves from mucus obstruction into non-resolving airway inflammation, bronchiectasis, and damage that impairs respiratory and fitness activity. Therefore, therapeutic strategies that promote resolution of airway inflammation in CF to alleviate the burden of airflow obstruction and improve physical capacity are of wide interest. Here, we report that the proresolving lipid mediator resolvin (Rv) D1 halts mucus-driven inflammation in CF human cells and in vivo. RvD1 dampened migration and pathogenic phenotypes of neutrophils from volunteers with CF as well as inflammatory signaling pathways of CF bronchial epithelial cells triggered by CF mucus. In mice overexpressing the β-subunit of the epithelial Na+ channel (βENaC) RvD1 administration prevented and reverted lung inflammation caused by mucus accumulation and promoted the resolution of pulmonary exacerbation caused by P. aeruginosa. RvD1 also significantly improved physical activity and energy expenditure that are impaired in βENaC mice compared to wild type littermates. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung disease and chronic inflammation associated with mucus obstruction and provide proof of concept for its potential therapeutic approach in FC.
2023-10-10 | GSE234839 | GEO