Inhibition of Metalloproteinase Activity Promotes PMVEC Barrier Function Under Septic Conditions
Notice bibliographique
Résumé
Background Sepsis is a life‐threatening human disease with significant mortality characterized by excessive inflammation, which can lead to endothelial dysfunction, microvascular injury and organ damage. During sepsis, endothelial cells, especially the pulmonary microvascular endothelial cells (PMVEC), become injured leading to loss of barrier function and accumulation of protein‐rich edematous fluid. Metalloproteinases, including the matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families, are capable of cleaving cell surface proteins, such as cell‐cell junctional proteins, suggesting a potential role in septic PMVEC barrier dysfunction. Metalloproteinase activity is regulated by the tissue inhibitors of metalloproteinases (TIMPs). Recent work in our lab found that PMVEC lacking TIMP3, a critical regulator of both MMP and ADAM activity, had increased permeability compared to wild type (WT) PMVEC. Hypothesis We hypothesize that PMVEC‐derived metalloproteinase activity will be increased under septic conditions and that vascular permeability will be reduced with the application of synthetic metalloproteinase inhibitors. Materials and Methods PMVEC isolated from WT and Timp3 −/− mice were stimulated with PBS (control) or cytomix (equimolar tumour necrosis factor α, interferon γ, and interleukin 1β) + lipopolysaccharide (LPS; septic) for 4 hours. Metalloproteinase activity was then assessed in the conditioned media and cell lysate, and trans‐PMVEC macromolecular flux was assessed using Evans blue‐labelled albumin. Additionally, PMVEC surface localization of VE‐cadherin (adherens junction) and claudin‐5 (tight junction) was assessed by immunofluorescence on WT and Timp3 −/− PMVEC. To confirm the role of metalloproteinases, WT and Timp3 −/− PMVEC were treated with synthetic metalloproteinase inhibitors. Results Analysis of metalloproteinase activity revealed increased MMP13 and ADAM17 activity in septic PMVEC and Timp3 −/− PMVEC leading to a loss of inter‐PMVEC junctional proteins and subsequent PMVEC barrier dysfunction. Importantly, the application of synthetic metalloproteinase inhibitors such as BB94, CL82198 and TAPI2 reduced the permeability and disruption of VE‐cadherin and claudin 5 under septic conditions. Discussion and conclusion Increased metalloproteinase activity under septic conditions is associated with disrupted inter‐PMVEC junctional protein localization and loss of barrier function suggesting metalloproteinases are critical mediators of septic PMVEC barrier dysfunction. Further, PMVEC‐derived TIMP3 appears to be an important regulator of PMVEC‐derived metalloproteinase activity as loss of TIMP3 is associated with increased metalloproteinase activity and subsequent PMVEC barrier dysfunction. Thus, these studies suggest that inhibition of metalloproteinase activity may promote PMVEC barrier function by reducing inter‐junctional protein degradation during sepsis and thereby reducing septic vascular permeability. Support or Funding Information OTSHeart and Stroke OGS
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 machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 source (Gemma direct ou Codex distillé), 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 ».