The role of aging on endothelial cell-cell junctions and pulmonary microvascular permeability
Bibliographic record
Abstract
Abstract Lung injury leads to pulmonary microvascular endothelial cell (PMVEC) damage, disruption of cell-cell junctions, and increased permeability. Previously, we demonstrated in a mechanical ventilation-induced model of lung injury that aging exacerbated pulmonary microvascular permeability. Based on this, we hypothesized that aging was associated with increased PMVEC barrier dysfunction due to impaired cell-cell junction integrity. PMVEC were isolated from young and aged mice and cultured to confluence in vitro . Barrier function and cell-cell junction integrity were assessed through electric cell-substrate impedance sensing, XPerT permeability assay, immunofluorescence, and western blot analysis. Further studies were conducted to examine alterations in the proteome, markers of inflammation, and actin cytoskeleton organization. To model injurious conditions, PMVEC were stimulated with inflammatory cytokines; permeability and actin cytoskeletal alterations were subsequently assessed. We observed increased basal permeability in PMVEC from aged mice, which was associated with disrupted cell-surface localization of the adherens junction protein, vascular endothelial (VE)-cadherin. Protein abundance of VE-cadherin was significantly increased with age; however, levels of the adapter protein, γ -catenin, and the tight junction protein, claudin-5, were decreased. Measures of inflammation, including cytokine expression and cell surface abundance of adhesion molecules, did not differ with age. Alterations in actin cytoskeleton organization, characterized by augmented presence of actin stress fibers, were observed in aged PMVEC. Under inflammatory conditions, permeability and actin stress fiber formation were exacerbated with age. It is concluded that aging predisposes PMVEC to elevated injury, due to inherent deficiencies in cell-cell junctions and barrier function, potentially mediated through altered actin cytoskeleton organization. New and Noteworthy Compared with pulmonary microvascular endothelial cells (PMVEC) from young mice, PMVEC isolated from aged mice had higher permeability, which was directly associated with impairments in cell-cell junctions. The higher permeability in aged PMVEC was not associated with augmented inflammatory signaling but was associated with actin cytoskeletal alterations. Following an inflammatory insult, PMVEC from aged mice had further exacerbated permeability. These findings may begin to highlight why older patients exhibit higher mortality during lung injury.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 source (direct Gemma or distilled Codex), 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".