Epithelial LIF signaling limits apoptosis and lung injury during bacterial pneumonia
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ABSTRACT:
PROVIDER: PRJNA744909 | ENA |
REPOSITORIES: ENA
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Project description:During bacterial pneumonia, alveolar epithelial cells are critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. While LIFR was detected on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing LIFR, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of LIFR. Sequencing data indicated that ATII cells were significantly impacted as a result of pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.
2022-02-17 | GSE179764 | GEO
Project description:Leukemia inhibitory factor (LIF) is amongst the IL-6 family cytokines expressed in the lungs during pneumonia. However, the function of endogenous LIF during pneumonia has never been explored. The purpose of this study was to determine the transcriptional response to pneumonia in the lungs and whether or how this response is influenced by LIF. Mice received intratracheal instillations of vehicle (PBS) or Escherichia coli (10^6 CFU). Control IgG or anti-LIF specific IgG was included in the instillate. 24 hours after the challenge, lungs were collected for RNA isolation and microarray analysis.
2012-04-26 | GSE34901 | GEO
Project description:Leukemia inhibitory factor (LIF) is amongst the IL-6 family cytokines expressed in the lungs during pneumonia. However, the function of endogenous LIF during pneumonia has never been explored. The purpose of this study was to determine the transcriptional response to pneumonia in the lungs and whether or how this response is influenced by LIF. Mice received intratracheal instillations of vehicle (PBS) or Escherichia coli (10^6 CFU). Control IgG or anti-LIF specific IgG was included in the instillate. 24 hours after the challenge, lungs were collected for RNA isolation and microarray analysis. RNA from 3 separate groups of mice (3 mice per group) was analyzed: 1) 24h Vehicle/control IgG-treated; 2) 24h E. coli/control IgG-treated; and 3) 24h E. coli/anti-LIF-specific IgG.
2012-04-25 | E-GEOD-34901 | biostudies-arrayexpress
Project description:Leukemia inhibitory factor (LIF) is a cytoprotective cytokine that reduces lung injury during pneumonia. The purpose of this study was to determine the influence of LIF on pneumonia-induced gene changes in lung epithelium. Mice received intratracheal instillations of vehicle (PBS) or Escherichia coli (10^6 CFU). Control IgG or anti-LIF specific IgG was included in the instillate. 6 hours after the challenge, lung epithelial cells (EpCAM+/CD45-) were sorted from enzymatic lung digests and used for RNA isolation and microarray analysis.
2022-02-17 | GSE179419 | GEO
Project description:Leukemia inhibitory factor (LIF) is a cytoprotective cytokine that reduces lung injury during pneumonia. The purpose of this study was to determine the influence of LIF on pneumonia-induced gene changes in lung epithelium. Mice received intratracheal instillations of vehicle (PBS) or Escherichia coli (10^6 CFU). Control IgG or anti-LIF specific IgG was included in the instillate. 24 hours after the challenge, lung epithelial cells (EpCAM+/CD45-) were sorted from enzymatic lung digests and used for RNA isolation and microarray analysis.
2022-02-17 | GSE179418 | GEO
Project description:Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly. Daily PAXgene samples for up to 5 days for; influenza A pneumonia patients (n=8), bacterial pneumonia patients (n=16), mixed bacterial and influenza A pneumonia patients (n=3), systemic inflammatory response patients (SIRS, n=13). Days 1 and 5 PAXgene samples for healthy control individuals
2012-08-14 | E-GEOD-40012 | biostudies-arrayexpress
Project description:C57BL/6 mice were intratracheally challenged for 24 hours with saline or E. coli (1 x 10^6 CFU) with or without LIF neutralization. Left lobes were collected and digested into single-cell suspensions for FACS. Equal ratios of CD45+ (leukocytes), CD45-EpCAM+ (epithelium), and CD45-EpCAM- (other) cells were pooled from a mouse undergoing each condition.
2022-02-17 | GSE179855 | GEO
Project description:Single-cell RNA-seq of lung cells following bacterial pneumonia with or without LIF blockade
| PRJNA745341 | ENA
Project description:Introduction: Diagnosis of severe influenza pneumonia remains challenging because of the lack of correlation between presence of influenza virus and patient’s clinical status. We conducted gene expression profiling in the whole blood of critically ill patients to identify a gene signature that would allow clinicians to distinguish influenza infection from other causes of severe respiratory failure (e.g. bacterial pneumonia, non-infective systemic inflammatory response syndrome). Methods: Whole blood samples were collected from critically ill individuals and assayed on Illumina HT-12 gene expression beadarrays. Differentially expressed genes were determined by linear mixed model analysis and over-represented biological pathways determined using GeneGo MetaCore. Results: The gene expression profile of H1N1 influenza A pneumonia was distinctly different from bacterial pneumonia and systemic inflammatory response syndrome. The influenza gene expression profile is characterized by up-regulation of genes from cell cycle regulation, apoptosis and DNA-damage response pathways. In contrast, no distinctive gene-expression signature was found in patients with bacterial pneumonia or systemic inflammatory response syndrome. The gene expression profile of influenza infection persisted through five days of follow-up. Furthermore, in patients with primary H1N1 influenza A infection who subsequently developed bacterial co-infection, the influenza gene-expression signature remained unaltered, despite the presence of a super-imposed bacterial infection. Conclusions: The whole blood expression profiling data indicates that the host response to influenza pneumonia is distinctly different from that caused by bacterial pathogens. This information may speed up identification of the cause of infection in patients presenting with severe respiratory failure, allowing appropriate patient care to be undertaken more rapidly.
2012-08-15 | GSE40012 | GEO
Project description:Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage fluid collected from mice at various timepoints of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB’s activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments.
2022-11-29 | GSE199707 | GEO