Regulation of neutrophil trafficking by the lipid mediators of inflammation
Bibliographic record
Abstract
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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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".