Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury.
Détails
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Accès restreint UNIL
Etat: Public
Version: de l'auteur⸱e
Licence: CC BY 4.0
Accès restreint UNIL
Etat: Public
Version: de l'auteur⸱e
Licence: CC BY 4.0
ID Serval
serval:BIB_265A0BAF1302
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Efficacy of Clinically Used PARP Inhibitors in a Murine Model of Acute Lung Injury.
Périodique
Cells
ISSN
2073-4409 (Electronic)
ISSN-L
2073-4409
Statut éditorial
Publié
Date de publication
26/11/2022
Peer-reviewed
Oui
Volume
11
Numéro
23
Pages
3789
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.
Mots-clé
Mice, Humans, Animals, Poly(ADP-ribose) Polymerase Inhibitors/pharmacology, Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use, Disease Models, Animal, Acute Lung Injury/drug therapy, Lung, Inflammation Mediators/pharmacology, Necrosis, cell death, cytokines, inflammation, olaparib
Pubmed
Web of science
Open Access
Oui
Création de la notice
19/12/2022 11:08
Dernière modification de la notice
23/01/2024 7:14