Inhibition of Recruitment and Activation of Neutrophils by Pyridazinone-Scaffold-Based Compounds

• Type of Material: Article
• Authors: Aurelie Moniot, Université de Reims; Julien Braux, Université de Reims; Renaud Siboni, Université de Reims; Christine Guillaume, Université de Reims; Sandra Audonnet, Université de Reims; Ingrid Allart-Simon, Université de Reims; Janos Sapi, Université de Reims; Rabindra Tirouvanziam, Emory University; Stephane Gerard, Université de Reims; Sophie C. Gangloff, Université de Reims; Frederic Velard, Université de Reims
• Language: English
• Date: 2022-07-01
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/ijms23137226
• Title of Journal or Parent Work: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• Volume: 23
• Issue: 13
• Keywords: phagocytosis; BIOLOGICAL EVALUATION; ROFLUMILAST; Chemistry; MIGRATION; INFLAMMATION; air pouch model; Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; APOPTOSIS; FRIEDEL-CRAFTS ALKYLATION; exocytosis; REDUCTION; DISEASE; Chemistry, Multidisciplinary; Physical Sciences; migration; DERIVATIVES; inflammation; RELEASE
• Research Categories: Biology, Molecular; Chemistry, General

Abstract

In inflammatory diseases, polymorphonuclear neutrophils (PMNs) are known to produce elevated levels of pro-inflammatory cytokines and proteases. To limit ensuing exacerbated cell responses and tissue damage, novel therapeutic agents are sought. 4aa and 4ba, two pyridazinone-scaffold-based phosphodiesterase-IV inhibitors are compared in vitro to zardaverine for their ability to: (1) modulate production of pro-inflammatory mediators, reactive oxygen species (ROS), and phagocytosis; (2) modulate degranulation by PMNs after transepithelial lung migration. Compound 4ba and zardaverine were tested in vivo for their ability to limit tissue recruitment of PMNs in a murine air pouch model. In vitro treatment of lipopolysaccharide-stimulated PMNs with compounds 4aa and 4ba inhibited the release of interleukin-8, tumor necrosis factor-α, and matrix metalloproteinase-9. PMNs phagocytic ability, but not ROS production, was reduced following treatment. Using a lung inflammation model, we proved that PMNs transmigration led to reduced expression of the CD16 phagocytic receptor, which was significantly blunted after treatment with compound 4ba or zardaverine. Using the murine air pouch model, LPS-induced PMNs recruitment was significantly decreased upon addition of compound 4ba or zardaverine. Our data suggest that new pyridazinone derivatives have therapeutic potential in inflammatory diseases by limiting tissue recruitment and activation of PMNs.