Investigation of the Role of Aging on Pulmonary Microvascular Endothelial Cell Barrier Function During Mechanical Ventilation
Notice bibliographique
Résumé
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.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».