Titre
Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Martins, V.
Auteure/Auteur
Santos, S.S.
Auteure/Auteur
Rodrigues, LOCP
Auteure/Auteur
Salomao, R.
Auteure/Auteur
Liaudet, L.
Auteure/Auteur
Szabo, C.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2073-4409
Statut éditorial
Publié
Date de publication
2022-11-26
Volume
11
Numéro
23
Première page
3789
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: epublish
Publication Status: epublish
Résumé
Poly(ADP-ribose) polymerase 1 (PARP1), as a potential target for the experimental therapy of acute lung injury (ALI), was identified over 20 years ago. However, clinical translation of this concept was not possible due to the lack of clinically useful PARP inhibitors. With the clinical introduction of several novel, ultrapotent PARP inhibitors, the concept of PARP inhibitor repurposing has re-emerged. Here, we evaluated the effect of 5 clinical-stage PARP inhibitors in oxidatively stressed cultured human epithelial cells and monocytes in vitro and demonstrated that all inhibitors (1-30 µM) provide a comparable degree of cytoprotection. Subsequent in vivo studies using a murine model of ALI compared the efficacy of olaparib and rucaparib. Both inhibitors (1-10 mg/kg) provided beneficial effects against lung extravasation and pro-inflammatory mediator production-both in pre- and post-treatment paradigms. The underlying mechanisms include protection against cell dysfunction/necrosis, inhibition of NF-kB and caspase 3 activation, suppression of the NLRP3 inflammasome, and the modulation of pro-inflammatory mediators. Importantly, the efficacy of PARP inhibitors was demonstrated without any potentiation of DNA damage, at least as assessed by the TUNEL method. These results support the concept that clinically approved PARP inhibitors may be repurposable for the experimental therapy of ALI.
PID Serval
serval:BIB_265A0BAF1302
PMID
Open Access
Oui
Date de création
2022-12-19T10:08:59.271Z
Date de création dans IRIS
2025-05-20T13:26:42Z
Fichier(s)![Vignette d'image]()
En cours de chargement...
Nom
36497049_BIB_265A0BAF1302.pdf
Version du manuscrit
preprint
Licence
https://creativecommons.org/licenses/by/4.0
Taille
43.85 MB
Format
Adobe PDF
PID Serval
serval:BIB_265A0BAF1302.P001
Somme de contrôle
(MD5):a1e454670bc8d5b6e592d92787b62502