CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

• Main Authors: Matheus Silverio Mattos, Maximiliano Ruben Ferrero, Lucas Kraemer, Gabriel Augusto Oliveira Lopes, Diego Carlos Reis, Geovanni Dantas Cassali, Fabricio Marcus Silva Oliveira, Laura Brandolini, Marcello Allegretti, Cristiana Couto Garcia, Marco Aurélio Martins, Mauro Martins Teixeira, Remo Castro Russo
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-10-01
• Series: Frontiers in Immunology
• Subjects: neutrophils (PMNs); asthma; fibrosis; chronic obstructive pulmonary disease; influenza A (H1N1)
• Online Access: https://www.frontiersin.org/article/10.3389/fimmu.2020.566953/full

RationaleIncreased IL-8 levels and neutrophil accumulation in the airways are common features found in patients affected by pulmonary diseases such as Asthma, Idiopathic Pulmonary Fibrosis, Influenza-A infection and COPD. Chronic neutrophilic inflammation is usually corticosteroid insensitive and may be relevant in the progression of those diseases.ObjectiveTo explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component.FindingsLadarixin was able to reduce the acute and chronic neutrophilic influx, also attenuating the Th2 eosinophil-dominated airway inflammation, tissue remodeling and airway hyperresponsiveness. Correspondingly, Ladarixin decreased bleomycin-induced neutrophilic inflammation and collagen deposition, as well as attenuated the corticosteroid resistant Th17 neutrophil-dominated airway inflammation and hyperresponsiveness, restoring corticosteroid sensitivity. Finally, Ladarixin reduced neutrophilic airway inflammation during cigarette smoke-induced corticosteroid resistant exacerbation of Influenza-A infection, improving lung function and mice survival.ConclusionCXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.