Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip
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ABSTRACT:
PROVIDER: PRJNA737154 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14799344_1.fastq.gz | Fastqsanger.gz | |||
| SRR14799344_2.fastq.gz | Fastqsanger.gz | |||
| SRR14799345_1.fastq.gz | Fastqsanger.gz | |||
| SRR14799345_2.fastq.gz | Fastqsanger.gz | |||
| SRR14799346_1.fastq.gz | Fastqsanger.gz |
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Project description:Mechanical forces associated with breathing play fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
2022-01-01 | GSE177862 | GEO
Project description:Mechanical forces associated with breathing play fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
2021-12-01 | GSE178382 | GEO
Project description:Mechanical forces associated with breathing play fundamental role in lung development and disease but the molecular pathways remain largely unknown. Here, we used a mechanically actuatable Human Lung Alveolus Chip that recapitulates human lung alveolar type I and type II cell differentiation, alveolar-capillary interface formation, and genome-wide gene expression profiles characteristic of the distal lung to investigate the role of physical forces associated with cyclic breathing motions in lung innate immune responses to viral infection. When the mechanically active Alveolus Chips are infected with influenza H3N2 virus, a cascade of host responses is elicited on-chip, including increased production of cytokines and expression of inflammation-associated genes in pulmonary epithelial and endothelial cells, resulting in enhanced recruitment of circulating immune cells as occurs during viral infection in vivo. Surprisingly, studies carried out in parallel with static chips revealed that physiological breathing motions suppress viral replication by activating protective innate immune responses in epithelial and endothelial cells. This is mediated at least in part through upregulation of S100 calcium-binding protein A7 (S100A7), which binds to the Receptor for Advanced Glycation End Products (RAGE), an inflammatory mediator that is most highly expressed in the lung alveolus in vivo. This mechano-immunological control mechanism is further supported by the finding that existing RAGE inhibitor drugs can suppress production of inflammatory cytokines in response to influenza virus infection in this model. S100A7-RAGE interactions and modulation of mechanical ventilation parameters could therefore serve as new targets for therapeutic intervention in patients infected with influenza and other potential pandemic viruses that cause life-threatening lung inflammation.
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Project description:Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip III
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Project description:Mechanical control of innate immune responses against viral infection revealed in a human Lung Alveolus Chip II
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Project description:Acute exposure to high-dose gamma radiation can result in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip lined by human lung alveolar epithelium interfaced with pulmonary endothelium (Lung Alveolus Chip) is used to model acute, early stage RILI in vitro. Both lung epithelium and endothelium exhibit DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6h of radiation exposure, and greater damage is observed in the endothelium. The alveolus chips are exposed to radiation injury at 16 Gy and shows effects that resemble the human lung greater than animal preclinical models. The Alveolus Chip is also used to evaluate the potential ability of two drugs to suppress the effects of acute RILI. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative approach for studying the molecular basis of acute RILI towards screening radiation countermeasure therapeutics.
2023-09-13 | GSE242706 | GEO
Project description:Acute exposure to high-dose gamma radiation often results in radiation-induced lung injury (RILI), characterized by acute pneumonitis and subsequent lung fibrosis. A microfluidic organ-on-a-chip device consisting of human lung alveolar epithelium and pulmonary endothelium (Lung Alveolus Chip) is used to recapitulate acute, early stage RILI in vitro. This RNA-seq data captures that both the lung epithelium and endothelium in this model capture key hallmarks of this disease particularly, DNA damage, cellular hypertrophy, upregulation of inflammatory cytokines, and loss of barrier function within 6h of radiation exposure. The data also suggests that radiation affects the alveolar endothelium more significantly than the epithelium. The alveolus chips are exposed to radiation injury at 16 Gy and shows effects that resemble the human lung greater than animal preclinical models. These data demonstrate that the Lung Alveolus Chip provides a human relevant alternative approach for studying the molecular basis of acute RILI towards screening radiation countermeasure therapeutics.
2023-09-11 | GSE242840 | GEO
Project description:The lung alveolus is the primary site of gas exchange in mammals. Within the alveolus, the alveolar type 2 (AT2) epithelial cell population generates surfactant to maintain alveolar structure and harbors a regenerative capacity to repair the alveolus after injury. We show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the AT2 cell population is critical for regenerating the alveolar niche. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a majority of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome, and functional phenotype with specific responsiveness to Wnt and FGF signaling that modulates differentiation and self-renewal, respectively. Importantly, human AEPs (hAEPs) can be isolated and characterized through a conserved surface marker and are required for human alveolar self-renewal and differentiation using alveolar organoid assays. Together, our findings show that AEPs are an evolutionarily conserved alveolar progenitor lineage essential for regenerating the alveolar niche in the mammalian lung.
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Project description:The lung alveolus is the primary site of gas exchange in mammals. Within the alveolus, the alveolar type 2 (AT2) epithelial cell population generates surfactant to maintain alveolar structure and harbors a regenerative capacity to repair the alveolus after injury. We show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the AT2 cell population is critical for regenerating the alveolar niche. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a majority of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome, and functional phenotype with specific responsiveness to Wnt and FGF signaling that modulates differentiation and self-renewal, respectively. Importantly, human AEPs (hAEPs) can be isolated and characterized through a conserved surface marker and are required for human alveolar self-renewal and differentiation using alveolar organoid assays. Together, our findings show that AEPs are an evolutionarily conserved alveolar progenitor lineage essential for regenerating the alveolar niche in the mammalian lung.
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