Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD
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ABSTRACT:
PROVIDER: PRJNA986830 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25003904.fastq.gz | Fastqsanger.gz | |||
| SRR25003905.fastq.gz | Fastqsanger.gz | |||
| SRR25003906.fastq.gz | Fastqsanger.gz | |||
| SRR25003907.fastq.gz | Fastqsanger.gz | |||
| SRR25003908.fastq.gz | Fastqsanger.gz |
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Project description:Alveolar epithelial type II cells (AEC2) strictly regulate lipid metabolism to maintain surfactant synthesis. A loss in AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking related lung disease, chronic obstructive pulmonary disease (COPD). It is unclear if smoking alters lipid synthesis in AEC2 cells and if altering lipid metabolism in AEC2 cells contributes to COPD development. In this study, high throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN) in AEC2 cells (FasniAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, more severe air-space enlargement and were more susceptible to age-induced emphysema. FasniAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins and polyunsaturated fatty acid containing-phospholipids, as well as increased BALF surface tension. FasniAEC2 mice exposed to CS also had higher markers of ferroptosis in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.
2023-08-22 | GSE235644 | GEO
Project description:Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.
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Project description:Background: When exposed to specific stimuli, macrophages exhibit distinct activation programs, M1 and M2 polarization, that define macrophage function as inflammatory/immune effectors or anti-inflammatory/tissue remodeling cells, respectively. Due to their position on the lung epithelial surface, alveolar macrophages (AM) directly interact with environmental stimuli such as cigarette smoke, the major risk factor for the development of chronic obstructive pulmonary disease (COPD). Based on the current paradigm that, in response to smoking, AM contribute to both inflammatory and tissue remodeling processes in the lung relevant to the pathogenesis of COPD, we hypothesized that chronic exposure to cigarette smoking activates both the M1 and M2 polarization programs in AM. Methods and Findings: To assess this hypothesis, global transcriptional profiling with TaqMan confirmation and flow cytometry analysis was carried out on AM obtained by bronchoalveolar lavage of 24 healthy nonsmokers, 34 healthy smokers and 12 smokers with COPD to assess the expression of 41 M1 genes and 32 M2 genes in each group. Contrary to our expectations, while there was up-regulation of some genes typical for M2-related phenotypes, AM of healthy smokers exhibited substantial suppression of M1-related inflammatory/immune genes. These M1- and M2-related changes progressed with the development of smoking-induced lung disease, with AM of smokers with COPD exhibiting further down-regulation of M1-related genes accompanied with further up-regulation of some M2-related genes. Conclusion: The data demonstrates that the modifications of the AM transcriptome associated with smoking result in a unique phenotype characterized by reprogramming of AM towards M1-deactivated partially M2-polarized macrophages and suggests that, while AM likely contribute to smoking-induced tissue remodeling, the role of AM in the early pathogenesis of smoking-induced COPD in humans is not inflammatory. This concept is a departure from the conventional concept that AM-mediated inflammation participates in the early derangements of the lung induced by smoking, and suggests a novel paradigm for conceptualizing COPD and developing new approaches to prevent the development of smoking-induced lung disease. Comparison of gene expression in alveolar macrophages of normal non-smokers and normal smokers and smokers with COPD
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2011-04-18 | E-GEOD-16972 | biostudies-arrayexpress
Project description:Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of morbidity and mortality in the world and is predicted to be the third leading cause of death. It is characterized by chronic airway inflammation, lung destruction and remodeling, resulting in irreversible airflow obstruction. We utilized single cell RNA-sequencing (scRNA-Seq) to identify ferroptotic differences and associated biological processes involved in the pathogenesis of COPD. We performed scRNA-Seq on lung tissue obtained from donors with non-COPD and mild-to-moderate COPD to identify disease-related genes within different cell types. We identified two populations of alveolar macrophages (AMs) in the human lung that were dysregulated in COPD patients. We discovered that M2-like AMs modulate susceptibility to ferroptosis by disrupting lipid and iron homeostasis both in vivo and in vitro. The discrepancy in sensitivity to ferroptosis can be determined and regulated by HO-1. In contrast, M1-like AMs showed the ability to attenuate oxidative stress and exert resistance to ferroptosis. In addition, the expression of genes within M2-like AMs is also involved in defects in phagocytosis and lysosome distortion. Present scRNA-seq transcriptomic analysis provides a rich data source to further explore lung health and disease, and the development of therapeutic strategies specifically targeting ferroptosis-sensitive alveolar macrophages might be used to develop therapeutic targets..
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