Cellular imbalance in proximal and distal lung of CFTR-/- sheep in utero and at birth.
Ontology highlight
ABSTRACT:
ORGANISM(S): Ovis aries
PROVIDER: GSE281174 | GEO | 2025/06/18
REPOSITORIES: GEO
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Project description:Much of our understanding of human lung development is based on earlier physiological studies in the sheep. Here we investigate lung development in wild-type sheep by transcriptomic analysis of proximal and distal lung tissue from day 65 to term (147 days). We also document the transcriptome of lung development at the same time points in the CF sheep model, enabling comparative studies of the impact of CF on the lung before birth,
2025-04-21 | GSE202019 | GEO
Project description:Cystic Fibrosis (CF) is associated with pathology in multiple tissues including the lung, digestive tract and reproductive system. Lung disease is primarily a post-natal event but other organs are affected before birth. Here we use the CF sheep model to investigate the initiation and progression of CF disease through gestation.
2023-02-14 | GSE202024 | GEO
Project description:Background: CFTR modulators will decrease some etiologies of inflammation in the CF airway; however, current data indicate that non-resolving airway infection and inflammation will persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish CF airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation require a better understanding of the cellular contributions to chronic CF airway disease, and how cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, and represent intriguing targets for focused therapies to dampen CF airway inflammation. Material and Methods: In order to characterize the inflammatory phenotype of CF blood monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq). Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA. Results: RNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional pathways were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including transcriptional modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine. These results demonstrate that ivacaftor causes acute changes in blood monocytes and plasma chemokines, and suggest that increased monocyte inflammatory signals and potentially improved trafficking to the lung contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of isolated blood monocytes in CF subjects.
2020-07-31 | GSE148076 | GEO
Project description:Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and/or causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild- type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an exciting opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop. Pig model of human CF lung disease
2010-09-17 | E-GEOD-21071 | biostudies-arrayexpress
Project description:Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use the sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. Transcriptomic evidence from bulk RNA-seq showed alterations in the CF pancreas by 65 days of gestation, which are accompanied by marked pathological changes by 80 days gestation. These include a profound fibrotic response, confirmed by immunostaining for COL1A1, SMA and SPARC, together with acinar destruction. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CF animals at 80- and 120-days gestation, as are activated stellate cells at term. This cellular imbalance likely has a pivotal role in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent CF pancreatic destruction.
2025-03-17 | GSE254375 | GEO
Project description:Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use the sheep model of CF (CFTR-/-) to examine the evolution of pancreatic disease through gestation. Transcriptomic evidence from bulk RNA-seq showed alterations in the CF pancreas by 65 days of gestation, which are accompanied by marked pathological changes by 80 days gestation. These include a profound fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar destruction. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CF animals at 80- and 120-days gestation, as are activated stellate cells at term. This cellular imbalance likely has a pivotal role in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent CF pancreatic destruction.
2025-03-17 | GSE254374 | GEO
Project description:Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and/or causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild- type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an exciting opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop.
2010-09-17 | GSE21071 | GEO
Project description:Cellular imbalance in proximal and distal lung of CFTR-/- sheep in utero and at birth.
| PRJNA1182671 | ENA
Project description:Cystic fibrosis (CF) is characterized by chronic inflammation and excessive cytokines secretion in the lung. Isogenic human CF bronchial epithelial (CFBE41o-) cell lines stably expressing wt-CFTR (WTBE) or F508del mutant (CFBE) are widely used tools in understanding responses to stimuli or drugs and CF pathogenesis in vitro. However, their intrinsic cellular differences in culture are unknown. Hence, we performed integrative analyses at protein, mRNA and chromatin levels on these isogenic cell lines cultured in submerged and transwell condition. CFBE and WTBE cells displayed different secretion patterns on IL-6, IL-8, CXCL1, CXCL10, and CCL5 . The ALI culture dramatically increased cytokines secretion in both cells. ATAC-seq results showed that CFBE cells exhibited higher genome-wide chromatin accessibility than WTBE cells in both culture methods, but the relative openness of cytokine genes between two cells varied individually. Differentially expressed genes between two cell lines from mRNA sequencing were highly concentrated in immunity-related pathways. While the mRNA stability of CXCL10 and CXCL1 exhibited the most significant differences between cell lines in SUB culture, most cytokines had comparable mRNA stabilities within same culture method. Moreover, polarization of cells via transwell culture remodeled the chromatin accessibility and transcriptome. This multilayered studies presents a comprehensive baseline activities of CFBE and WTBE cells, further facilitating their usage and data interpretation as CF cell models.
2022-03-01 | GSE186918 | GEO
Project description:This study performed single-cell RNA sequencing (scRNA-seq) analyses on lung-lavaged cells from macrophage-specific cystic fibrosis (Mac-CF) mice and congenic wild-type (WT) mice that had been challeged with Pseudomonas aeruginsa (PsA) for different time points (1, 3 and 5 days). Differences in global gene transcription were interrogated and compared. Results demonstrate that CFTR loss of function in macrophages altered the cell transcriptional program that mostly affected mitochondrial respiration, immune responses, and cellular antioxidant system. Thus, loss of CFTR function in macrophages influences the cell homeostasis, leading to a dysregulated cellular response to infection that may exacerbate CF lung disease.
2023-11-15 | GSE233733 | GEO