Alveolar Macrophage Transcriptional Programs are Associated with Ventilator-Free Days in Acute Respiratory Distress Syndrome
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PROVIDER: PRJNA479383 | ENA |
REPOSITORIES: ENA
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Project description:Rationale: Serial measurements of genome-wide transcriptional changes in alveolar macrophages (AMs) in patients with acute respiratory distress syndrome (ARDS) could identify dynamic biologic processes that are associated with clinical outcomes. Objectives: To identify associations between AM transcriptional programs and the composite endpoint of ventilator-free days (VFDs) over the course of ARDS. Methods: We performed unbiased genome-wide transcriptional profiling of AMs purified from bronchoalveolar lavage fluid collected from patients with ARDS. Cells were obtained at baseline (Day 1), Day 4, and Day 8 after ARDS onset. We assessed pathway enrichment in subjects with VFDs > 0 (VFD-Extubated/Alive) versus VFDs = 0 (VFD-Intubated/Dead) at each time point. Measurements and Main Results: We found highly divergent AM transcriptional patterns at all time points between ARDS patients based on their VFD status (FDR < 0.05). “M1-like” and pro-inflammatory gene sets such as IL-6-JAK-STAT signaling were significantly enriched in AMs isolated on Day 1 in VFD-Extubated/Alive versus VFD-Intubated/Dead subjects. In contrast, many of these same gene sets were associated with the VFD-Intubated/Dead subjects on Day 8. In patients who had samples from each time point, we identified multiple AM gene clusters whose temporal expression patterns were associated with VFD status. The relationship between AM expression profiles and VFDs was distinct in subjects with Direct (pulmonary) versus Indirect (extrapulmonary) ARDS. Conclusion: Clinically meaningful outcomes over the course of ARDS are associated with highly distinct AM transcriptional programs. Our findings suggest that interventions targeting the alveolar immune response should be tested within strictly defined time periods.
2019-03-31 | GSE116560 | GEO
Project description:Rationale: Serial measurements of genome-wide transcriptional changes in alveolar macrophages (AM) and peripheral blood monocytes (PBM) from patients with acute respiratory distress (ARDS) could clarify the biologic programs activated in ARDS and the relationship of these changes to clinical outcomes. Objectives: To identify transcriptional programs activated in purified AM and PBM over the course of ARDS, and determine the relationship of these programs with patient outcomes. Methods: We performed transcriptional profiling of total RNA isolated from AMs and PBMs purified from bronchoalveolar lavage fluid (BALF) and peripheral blood respectively, collected from patients (n = 26) with ARDS previously enrolled in a phase-II clinical trial. Cells were obtained at baseline (day 0) after enrollment. Measurements and Main Results: Using an unbiased gene set enrichment analysis (GSEA), we found highly divergent patterns of gene expression in AMs and PBMs. Notably, immuno-inflammatory gene sets were enriched in AMs isolated on day 0 in those who survived and had more ventilator-free days (VFD); however, this association between inflammatory and immune gene sets and good outcomes was not seen in PBMs. Conclusion: Transcriptional responses during ARDS are remarkably different between AMs and PBMs. Rationale: Serial measurements of genome-wide transcriptional changes in alveolar macrophages (AM) and peripheral blood monocytes (PBM) from patients with acute respiratory distress (ARDS) could clarify the biologic programs activated in ARDS and the relationship of these changes to clinical outcomes. Objectives: To identify transcriptional programs activated in purified AM and PBM over the course of ARDS, and determine the relationship of these programs with patient outcomes. Methods: We performed transcriptional profiling of total RNA isolated from AMs and PBMs purified from bronchoalveolar lavage fluid and peripheral blood respectively, collected from patients (n = 26) with ARDS previously enrolled in a phase-II clinical trial. Cells were obtained at baseline (day 0) after enrollment. Measurements and Main Results: Using an unbiased gene set enrichment analysis (GSEA), we found highly divergent patterns of gene expression in AMs and PBMs. Notably, immuno-inflammatory gene sets were enriched in AM isolated on day 0 in those who survived and had more ventilator-free days (VFD); however, this association between inflammatory and immune gene sets and good outcomes was not seen in PBMs. Conclusion: Transcriptional responses during ARDS are remarkably different between AM and PBM.
2017-04-30 | GSE89953 | GEO
Project description:Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) regulates numerous intracellular signaling pathways involved in inflammation and apoptosis. We hypothesized that genetic variation in MAP3K1 might be associated with outcomes in patients with acute respiratory distress syndrome (ARDS), and that these variants would alter MAP3K1-mediated changes in inflammation and transcriptional regulation. To test this hypothesis, we genotyped single-nucleotide polymorphisms covering linkage disequilibrium bins in MAP3K1 in 306 subjects with ARDS from the ARDSNet FACTT (Fluid and Catheter Treatment Trial) study, and tested for associations between MAP3K1 single-nucleotide polymorphisms and ventilator-free days (VFDs) and mortality. We then validated these associations in a separate cohort of 241 patients with ARDS from Harborview Medical Center (Seattle, WA). We found the variant allele of rs832582 (MAP3K1906Val) was significantly associated with decreased VFDs using multivariate linear regression (-6.1 d, false discovery rate?=?0.06) in the FACTT cohort. In the Harborview Medical Center cohort, subjects homozygous for MAP3K1906Val also had decreased VFDs (-15.1 d, false discovery rate?<?0.01), and increased 28-day mortality (all subjects homozygous for the rare allele died). In whole blood stimulated with various innate immune agonists ex vivo, MAP3K1906Val was associated with increased IL-1?, IL-6, IL-8, monocyte chemoattractant protein 1, and TNF-? production. Transcriptome analysis of whole blood stimulated with Toll-like receptor 4 agonist ex vivo demonstrated enrichment of inflammatory gene sets in subjects homozygous for MAP3K1906Val. Our findings show a robust association between the variant allele of rs832582 (MAP3K1906Val) and decreased VFDs in patients with ARDS and suggest that this variant may predispose individuals to a greater inflammatory response.
| S-EPMC5941309 | biostudies-literature
Project description:Proteasomes are a critical component of quality control that regulates turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Though pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Targeted deletion of RPT3 in AT2 cells resulted in 26S proteasome dysfunction, leading to augmented cell stress and death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome. This study underscores the need for further investigation into the differential effect of proteasome inhibition in lung cell types.
2019-08-29 | GSE123873 | GEO
Project description:ObjectivesThere is limited evidence on the impact of protocolized ventilator weaning in pediatric acute respiratory distress syndrome, despite utilization in clinical trials and clinical care. We aimed to determine whether protocolized ventilator weaning shortens mechanical ventilation duration and PICU length of stay in pediatric acute respiratory distress syndrome survivors.DesignSecondary analysis of a prospective pediatric acute respiratory distress syndrome (Berlin definition) cohort from July 2011 to June 2019 analyzed using interrupted time series analysis pre- and postimplementations of a ventilator-weaning pathway. We compared duration of invasive ventilation and PICU length of stay in survivors before and after implementation of a ventilator-weaning pathway. We excluded PICU nonsurvivors and subjects with greater than 100 ventilator days.SettingLarge academic tertiary-care PICU.PatientsChildren with acute respiratory distress syndrome who survived to PICU discharge with less than or equal to 100 days of invasive mechanical ventilation.InterventionsImplementation of a ventilator-weaning pathway on May 2016.Measurements and main resultsOf 723 children with acute respiratory distress syndrome, 132 subjects died and six subjects with ventilation greater than 100 days were excluded. Of the remaining 585 subjects, 375 subjects had acute respiratory distress syndrome prior to pathway intervention and 210 after. Patients in the preintervention epoch were younger, more likely to have infectious acute respiratory distress syndrome, and had increased use of alternative ventilator modes. Pathway adoption was rapid and sustained. Controlling for temporality, pathway implementation was associated with a decrease of a median 3.6 ventilator days (95% CI, -5.4 to -1.7; p < 0.001). There was no change in the reintubation rates. Results were robust to multiple sensitivity analyses adjusting for confounders.ConclusionsVentilator-weaning pathway implementation shortened invasive ventilation duration in pediatric acute respiratory distress syndrome survivors with no change in reintubation. The effect size of this intervention was comparable with those targeted in acute respiratory distress syndrome trials.
| S-EPMC7854887 | biostudies-literature
Project description:Respiratory distress is one of the major causes of the high mortality rate in neonatal cloned animals. Although some therapeutic methods have been used to improve the survival of cloned neonatal animals, the mechanisms of their neonatal respiratory distress lacked thorough investigation. Pathological analyses including necropsy and histology were implemented to determine the precise disease phenotypes, by which not fully dilated lungs, alveolar collapse and thickened alveolar walls were detected in neonatal cloned cows dying of respiratory distress compared to naturally conceived neonatal cows. In addition, we compared mRNA expression profiles between the two groups and differentially expressed genes (DEGs) have been achieved. Based on DEGs, GO and KEGG pathway enrichment analyses were performed, which showed that processes and pathways associated with surfactant homeostasis were significantly enriched between the two groups (p < 0.05).
2019-10-14 | GSE88912 | GEO
Project description:WT mice and claudin 4 KO mice were exposed to ventilator-induced lung injury (VILI) for 2 hours. We found that in some Cldn4 KO mice, injury was similar to WT, while in others, injury was higher, as assessed by amount of protein leak into broncho-alveolar lavage fluid. We performed RNAseq to find which genes were responsible for higher injury in Cldn4 KO mice. WT mice and claudin 4 KO mice were exposed to ventilator-induced lung injury (VILI) for 2 hours. RNA were extracted from whole lungs and RNA sequencing was performed. The samples are (all in duplicates): WT no VILI, Cldn4 KO no VILI, WT VILI, Cldn4 KO VILI with similar injury to WT (Cldn4 KOlow), and Cldn4 KO VILI with higher injury than WT (Cldn4 KOhigh)
2014-11-04 | E-GEOD-50927 | biostudies-arrayexpress
Project description:WT mice and claudin 4 KO mice were exposed to ventilator-induced lung injury (VILI) for 2 hours. We found that in some Cldn4 KO mice, injury was similar to WT, while in others, injury was higher, as assessed by amount of protein leak into broncho-alveolar lavage fluid. We performed RNAseq to find which genes were responsible for higher injury in Cldn4 KO mice.
2014-11-04 | GSE50927 | GEO
Project description:Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the "net effect" of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other "failure-free day" composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student's t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other "failure-free day" constructs, should also be accompanied by an examination of the components.
| S-EPMC6812447 | biostudies-literature
Project description:Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure yet has few pharmacologic therapies, reflecting the mechanistic heterogeneity of lung injury. We hypothesized that damage to the alveolar epithelial glycocalyx, a layer of glycosaminoglycans interposed between the epithelium and surfactant, contributes to lung injury in ARDS patients. Using mass spectrometry of airspace fluid noninvasively collected from mechanically-ventilated patients, we found that airspace glycosaminoglycan shedding (an index of glycocalyx degradation) occurred predominantly in patients with direct lung injury and was associated with duration of mechanical ventilation. Male patients had increased shedding which correlated with airspace concentrations of matrix metalloproteinases. Selective epithelial glycocalyx degradation in mice was sufficient to induce surfactant dysfunction, a key characteristic of ARDS, leading to microatelectasis and decreased lung compliance. Rapid colorimetric quantification of airspace glycosaminoglycans was feasible and could provide point-of-care prognostic information to clinicians and/or be used for predictive enrichment in clinical trials.
2021-12-07 | GSE186705 | GEO