Regulation of neutrophil trafficking by the lipid mediators of inflammation
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Notice bibliographique
Résumé
The lipid mediators of inflammation include platelet-activating factor (PAF) and several classes of metabolites of arachidonic acid derived from the cyclooxygenase (prostaglandins and thrombox-anes) and lipoxygenase pathways, such as leukotrienes (LTs) and lipox-ins. Of these lipid mediators, LTs and PAF are potent agonists of leukocytes and endothelial cells and show important proinflammatory properties. Several elegant studies have recently provided strong support for a role of one of these mediators, LTB 4 , in animal models of rheumatoid arthritis [ 1 – 3 ]. Interestingly, LTB 4 , LTC 4 /LTD 4 and PAF are concomitantly generated at the blood–endothelium interface when neutrophils bind to activated endothelial cells at inflammatory sites in vivo and are exposed to a chemoattractant. The hypothesis explored in this project is that the three classes of lipid mediators collectively and synergistically act to promote and facilitate neutrophil extravasation and accumulation at inflammatory sites. The hypothesis also implicates that, given the high level of redundancy in the abilities of the three lipid mediators to activate neutrophils and endothelial cells, the blockade of one of these mediators can only have a modest and incomplete inhibitory effect on neutrophil extravasation. The objective of these studies is therefore to compare the role of each individual mediator and the collective effect of the three mediators in regulating neutrophil trafficking. Another objective is to assess whether or not the combined use of antagonists to the three classes of mediators could result in a stronger inhibitory effect on neutrophil trafficking. The studies are performed using potent and selective LTB 4 , LTD 4 and PAF antagonists in both in vitro and in vivo models. The separate and collective role of the three classes of lipid mediators will be investigated in the migration of human neutrophils through a monolayer of human endothelial cells grown on a gel of extracellular matrix proteins. The studies also involve the use of models of dermal inflammation in rats and rabbits and the mouse air pouch model. The results show that, in the various models tested, neutrophil migration elicited by proinflammatory agents such as IL-1, tumor necrosis factor alpha and lipopolysaccharide is generally decreased by LTB 4 or PAF antagonists, and that the combination of both antagonists results in a greater inhibitory effect, supporting the concept that several lipid mediators generated locally (at the blood–endothelium interface and/or at inflammatory sites) regulate neutrophil trafficking. Additional experiments involving antagonists to the three classes of lipid mediators, as well as LTB 4 and PAF receptor knockout mice, are in progress.
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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 | 0,001 | 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 | 0,001 |
| 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 découle