Investigation of the Role of Aging on Pulmonary Microvascular Endothelial Cell Barrier Function During Mechanical Ventilation
Bibliographic record
Abstract
Elderly individuals have substantially elevated morbidity and mortality following pulmonary insult that require mechanical ventilation (MV) to sustain respiratory function. It is not known if an altered response to MV contributes to the worsened outcomes in the elderly. MV is associated with injury to pulmonary microvascular endothelial cells (PMVEC), leading to a compromised vascular barrier, and fluid and protein leakage within the tissue. However, the precise impact that age has on the vascular endothelium during MV is unknown. We hypothesized that aging augments PMVEC barrier dysfunction during MV. To address this hypothesis, young and aged mice were ventilated at a tidal volume of 20 mL/kg for 3 hours. To assess microvascular permeability, lungs were lavaged and abundance of the serum protein, immunoglobulin M, within the lavage fluid was measured. Lung tissue was dissociated into single cells and RNA was collected for single-cell RNA sequencing (scRNAseq). Subsequent analysis was performed using the Seurat package in R to give insight into the role of specific cell types, with a particular emphasis on microvascular endothelial cells. To directly assess molecular mechanisms directly in the cells, PMVEC were isolated from a separate cohort of non-ventilated young and aged mice and cultured in vitro. Cells were grown to confluency, then assessed for barrier integrity by Evans blue-labelled albumin leak across monolayers and immunofluorescence staining of cell junctional adherens and tight junction proteins, VE-cadherin and claudin-5. Compared to young, aged-ventilated animals had a significant increase in immunoglobulin M in their lavage fluid. Analysis of scRNAseq data revealed more robust activation and inflammation in the endothelial cells from aged animals following MV. Endothelial monolayers from aged animals in vitro exhibited a significant increase in albumin flux, which was associated with poor VE-cadherin and claudin-5 junction formation. In conclusion, PMVEC from aged mice exhibit compromised barrier function, leading to augmented permeability following MV. The age-dependent loss in barrier function appears to be due to an impaired ability to re-establish functional cell-cell junctions. These findings suggest that the aged vascular barrier is more susceptible to injury from MV, due to impaired PMVEC cell-cell junction integrity. Our results may highlight molecular pathways involved in predisposing aged individuals to worsened outcomes during MV, which can help in developing targeted therapeutics. Funded by Lawson Health Research Institute, CIHR, the Ontario Graduate Scholarship, and Western University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".