Therapeutic Intervention Targeting Mucosal Thrombin Or Protease‐Activated‐Receptor 1 Are Protective Against Colitis
Notice bibliographique
Résumé
Background Current therapies for Inflammatory Bowel Disease (IBD) are unsatisfactory for proper tissue healing. Serine proteases belong to locally produced host factors that can fuel inflammatory processes in tissue from IBD patients, in part through activation of Protease‐Activated Receptors (PAR). We have recently discovered that intestinal epithelium was able to produce active thrombin, suggesting that mucosa itself could be an important source of high thrombin in IBD. Objectives We first aimed to determine whether mucosal thrombin was upregulated in animal models of colitis and in tissues from IBD patients. We then determined whether local thrombin upregulation could contribute to local tissue malfunctions. Finally, we evaluated therapeutic feasibility of local delivering of either direct thrombin inhibitors or PAR antagonist in animal models of colitis. Methods Colonic tissue samples were obtained from diagnosed IBD patients undergoing colonoscopy at the Toulouse Hospital. Colitis was induced by administering trinitrobenzene sulfonic acid (TNBS) in the colon of Wistar rats or C57Bl6 mice. Human tissue collection and animal procedures received ethical approval from local ethic committees. Thrombin (100 U/ml, 10 days), direct thrombin inhibitor (dabigatran, 1 μg/kg, 4 days) and PAR1 antagonist (Vorapaxar, 2.5 mg/kg, 7 days) were administered in the colon of healthy or TNBS animals under light anesthesia. At time of the sacrifice, colonic tissues were harvested and disease severity was assessed. Thrombin expression was detected using PCR, western blot and immunofluorescence. Thrombin activity was quantified in tissue supernatants using specific enzymatic assays. Results We confirmed an increased thrombin protein expression in human mucosal tissue by immunofluorescence and western blots. We found that some, but not all, forms of active thrombin were upregulated, particularly in tissues from Crohn’s disease patients. As observed in human, we found that increased thrombin mRNA expression and activity is also a feature of colitis in animal models of colitis. We demonstrated in vivo that colonic exposure to high dose of active thrombin can cause mucosal damage and tissue dysfunctions. Specific inhibition of thrombin activity, and PAR1 antagonists prevent some intestinal damage in TNBS colitis. Conclusions In this study, using both animal models and human IBD tissues, we showed that upregulation of mucosal thrombin alone can lead to inflammatory insults. We propose that targeting downstream events from high thrombin activity, rather than inhibiting thrombin directly, might be a better option for IBD because mucosal thrombin at low dose plays an important role on maintaining tissue homeostasis. Considering these promising preclinical results on PAR1 antagonist, future clinical studies in IBD patients could therefore be rapidly envisioned, particularly in patients with the strongest upregulation of thrombin activity.
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) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 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 ».