Accumulation of myeloid lineage cells is mapping out liver fibrosis post injury: a targetable lesion using Ketanserin
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Notice bibliographique
Résumé
Liver fibrosis is problematic after persistent injury. However, little is known about its response to an acute insult. Accumulation of myeloid lineage cells contributes into the promotion and resolution of inflammation and fibrosis. Using Cre-transgenic mice that specifically mark myeloid lineage cells with EYFP and burn as a model of acute systemic injury, we investigated the role of myeloid lineage cells in the liver after acute injury. Our data show that thermal injury in mice (30% total body surface area) induces fibrosis predominantly around portal venules whereas myeloid cells are enriched throughout the liver. The fibrosis peaks around 1–2 weeks post injury and resolves by week 3. Ablating myeloid cells led to lower fibrosis. Through FACS sorting, we isolated myeloid lineage cells (EYFP +ve cells) from injured animals and from the control uninjured animals and subjected the extracted RNA from these cells to microarray analysis. Microarray analysis revealed an inflammatory signature for EYFP +ve cells isolated from injured animals in comparison with control cells. Moreover, it showed modulation of components of the serotonin (5-HT) pathway in myeloid cells. Antagonizing the 5HT2A/2C receptor decreased fibrosis in thermally injured mice by skewing macrophages away from their pro-fibrotic phenotype. Macrophages conditioned with Ketanserin showed a lower pro-fibrotic phenotype in a co-culture system with mesenchymal cells. There is a spatiotemporal pattern in liver fibrosis post-thermal injury, which is associated with the influx of myeloid cells. Treating mice with a 5HT2A/2C receptor antagonist promotes an anti-fibrotic effect, through modulating the phenotype of macrophages. A drug that affects serotonin pathway in the liver following systemic injury could help limit damage caused by fibrosis. Severe burn injuries can result in liver fibrosis, the over-production of connective tissues promoted by pro-inflammatory immune cells, including those derived from bone marrow myeloid cells. Chronic fibrosis can cause tissue dysfunction and extensive scarring which can contribute into liver dysfunction. In experiments on mice, Saeid Amini-Nik and Marc Jeschke at the University of Toronto, Canada, and co-workers demonstrated that myeloid cells are enriched in the liver after thermal injury, with a phenotype reminiscent of inflammatory macrophages. Treating the mice with a drug called Ketanserin, which targets serotonin pathway, altered the myeloid-derived immune cells so that they were less likely to cause fibrosis. This suggests a possible therapy for liver fibrosis post-injury.
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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) | 0,001 | 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) | 0,001 | 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 découle