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

• Published in: Frontiers in immunology Vol. 11; p. 566953
• Main Authors: Mattos, Matheus Silverio, Ferrero, Maximiliano Ruben, Kraemer, Lucas, Lopes, Gabriel Augusto Oliveira, Reis, Diego Carlos, Cassali, Geovanni Dantas, Oliveira, Fabricio Marcus Silva, Brandolini, Laura, Allegretti, Marcello, Garcia, Cristiana Couto, Martins, Marco Aurélio, Teixeira, Mauro Martins, Russo, Remo Castro
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 02.10.2020
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; asthma; Asthma - drug therapy; Asthma - etiology; Asthma - metabolism; Asthma - pathology; Biomarkers; Biopsy; Bleomycin - adverse effects; chronic obstructive pulmonary disease; Cytokines - metabolism; Disease Models, Animal; Disease Progression; Disease Susceptibility; Eosinophils - immunology; Eosinophils - metabolism; Female; Fibrosis; Immunohistochemistry; Immunology; influenza A (H1N1); Leukocytes; Male; Mice; Mice, Knockout; neutrophils (PMNs); Neutrophils - immunology; Neutrophils - metabolism; Ovalbumin - adverse effects; Oxidation-Reduction; Receptors, Interleukin-8A - antagonists & inhibitors; Receptors, Interleukin-8B - antagonists & inhibitors; Respiratory Hypersensitivity - etiology; Respiratory Hypersensitivity - metabolism; Respiratory Hypersensitivity - pathology; Respiratory Tract Diseases - drug therapy; Respiratory Tract Diseases - etiology; Respiratory Tract Diseases - metabolism; Respiratory Tract Diseases - pathology; Sulfonamides - pharmacology; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; influenza A (H1N1); asthma; fibrosis; neutrophils (PMNs); chronic obstructive pulmonary disease
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2020.566953

Increased 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. To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component. Ladarixin 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. CXCR1/2 antagonist Ladarixin offers a new strategy for therapeutic treatment of acute and chronic neutrophilic airway inflammation, even in the context of corticosteroid-insensitivity.