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:Intraluminal obstruction produces chronic airway epithelial hypoxia. We investigated how chronic airway epithelial hypoxia and inflammatory stimuli interact in human bronchial epithelial (HBE) cultures and resected human bronchiectatic lungs to produce the diseased epithelial environment characteristic of muco-obstructive diseases. HBE cultures were exposed to normoxia or hypoxia (1% O₂) for 4 days, and concurrently treated with supernatants from cystic fibrosis (CF) lung-derived mucopurulent material (SMM) or PBS for 5 days. Bulk RNA-sequencing was perfomed. Results: Hypoxia and SMM regulated largely separate transcriptional programmes regardless of treatment order. PTGS2 (COX2) and CCL20 represented a small number of genes additively upregulated by both hypoxia and SMM. Conclusion: Chronic hypoxia and inflammation regulated distinct genes/pathways that combine to produce complex diseased environments in muco-obstructed airways.
2026-08-17 | GSE314038 | GEO
Project description:Cystic fibrosis (CF) is a multisystemic, autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene with the majority of morbidity and mortality extending from lung disease. In this study, we leveraged single-cell transcriptional analyses to characterize the immune and airway epithelial cell populations in minimally invasive respiratory specimens obtained from pediatric patients with CF and pediatric non-CF controls at the time of clinically indicated flexible bronchoscopy. We focused on the pediatric population in an effort to better understand the early pathophysiology of CF lung disease. Through our approach, we provide insights into the composition of and functional changes within the immune and airway epithelial cell populations in the pediatric CF lung. Understanding the early pathophysiology of CF lung disease, including the changes present in the early cycles of airway infection, inflammation, and tissue damage, may reveal new potential therapeutic targets for CF lung disease.
2025-12-10 | GSE271984 | 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: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:Several muco-obstructive lung diseases in humans, including cystic fibrosis (CF), feature the chronic recruitment of blood leukocytes and their reprogramming within the lumen of small airways to drive pathological adaptations such as altered immune mediator secretion and defective killing of bacteria. To investigate these mechanisms, we engineered a biomimetic model in which primary human blood monocytes migrate through a human small airway epithelium, andepithelium and differentiate into macrophages upon 4-day exposure to macrophage colony-stimulating factor. We observed that airway-recruited monocytes (ArMos) obtained with the control chemoattractant C-C motif ligand 2 (CCL2) altered their transcriptome and secretome upon transmigration, and further upon differentiation into airway-recruited macrophages (ArMas), as compared to circulating monocytes. We observed specific additional alterations in transcriptomic and secretomic properties of ArMos and ArMas when they were conditioned in CF airway supernatant (derived from cell- and bacteria-free sputum) [CFASN], compared CCL2 conditions. Critically, CF ArMas (but not CF ArMos), showed a much reduced ability to kill P. aeruginosa, a common CF pathogen. These findings extend prior studies on small airway-recruited neutrophils, and identify immune tolerance by macrophages as one underlying cause of bacterial colonization in CF. This biomimetic model support further mechanistic and preclinical investigations of small airway-recruited monocytes and macrophages in CF and other diseases featuring chronic inflammation and infection, like non-CF bronchiectasis, and chronic obstructive pulmonary disease.
2025-12-01 | GSE311629 | 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:Muco-Obstructive Lung Disease Exhibits Distinct Hypoxic and Inflammatory Airway Epithelial Gene Pathways
| PRJNA1389472 | ENA
Project description:Muco-Obstructive Lung Disease Exhibits Distinct Hypoxic and Inflammatory Airway Epithelial Gene Pathways
| PRJNA1389641 | ENA