Protease activated receptor 2 deficiency in alveolar macrophages impairs cAMP generation leading to NFAT‐dependent pro‐inflammatory signalling and lung injury
Notice bibliographique
Résumé
Endotoxin (lipopolysaccharide [LPS]) is well known to induce intravascular coagulation during sepsis which may lead to multi‐organ failure and death. Protease Activated Receptor ( Par ) 1 and 2 expressed on several lung cell types can mediate crosstalk between coagulation and inflammation during endotoxemia but the mechanism remains unclear. Here, we exposed Par1 − / − , Par2 − / − and WT mice to nebulized LPS to address the relative roles of PAR1 versus PAR2 in modulating lung vascular injury caused by endotoxin LPS. We observed that LPS failed to induce lung injury in Par1 − / − mice while it resulted in unresolvable edema formation and neutrophilic injury in Par2 − / − mice. Also, Par2 − / − mice, showed significant increase in the expression of pro‐inflammatory cytokines in bronchoalveolar lavage. We showed that transplantation of bone marrow from WT mice into Par2 − / − mice resolved inflammatory injury in Par2 − / − mice indicating haematopoietic PAR2 as a critical factor mediating resolution of inflammatory lung injury. Additionally, depletion of alveolar macrophages using intratracheally ( i.t) clodronate following injury augmented lung injury in WT mice indicating PAR2 functioned by dampening alveolar macrophage activity. Since PAR2 has been shown to reverse PAR1 signalling and can be activated by thrombin directly, we next assessed if LPS‐induced thrombin generation activated PAR2 that then resolved edema formation. We delivered WT‐Par2 cDNA or mutated Par2 cDNA resistant to thrombin cleavage in Par2 − / − mice i.t. using liposomes and assessed lung edema following LPS challenge. We found that Par2 − / − mice transducing WT‐PAR2 resolved edema formation but this response was absent in mice expressing mutant PAR2 cDNA indicating that LPS induced thrombin generation activates PAR1 to mediate lung injury which is resolved following delayed activation of PAR2 by thrombin . Because PAR2 induces the generation of cAMP and Ca 2+ mobilization we assessed the generation of these second messengers in bone marrow derived macrophages (BMDM) from WT and Par2 − / − mice. We found that thrombin significantly increased cAMP levels in WT‐BMDM but not in Par2 − / − BMDM. This reduction was not due to insufficient activation of Gs or phosphodiesterase as foskolin and rollipram similarly altered cAMP levels in WT and Par2 − / − BMDM. Additionally, we found that loss of Par2 activated Ca 2+ entry into macrophages through transient receptor potential vanniloid channel (TRPV4) which reverted back to WT levels following addition of dibutryl cAMP. Since Ca 2+ entry induces NFAT transcriptional activity, we assessed the role of PAR2 in dampening inflammatory signaling and noted that loss of PAR2 increased phosphorylation of p65‐NFκB via NFAT activation. Rescuing cAMP levels diminished the phosphorylation of p65‐NFκB and NFAT activity and thereby inflammatory cytokine generation. These studies demonstrate the critical role of PAR2 activation in alveolar macrophages in resolving lung injury by inducing cAMP generation which in turn suppresses Ca 2+ ‐dependent inflammatory signalling by NFAT. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| 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 | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».