Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Immunology, neutrophils (PMNs), asthma, fibrosis, chronic obstructive pulmonary disease, IDIOPATHIC PULMONARY-FIBROSIS, SEVERE ASTHMA, LUNG-FUNCTION, RECRUITMENT, ANTAGONIST, CHEMOKINE, INTERLEUKIN-8, EXPRESSION, RECEPTORS, PATHOGENESIS, influenza A (H1N1), Animals, Anti-Inflammatory Agents, Asthma, Biomarkers, Biopsy, Bleomycin, Cytokines, Disease Models, Animal, Disease Progression, Disease Susceptibility, Eosinophils, Female, Fibrosis, Immunohistochemistry, Leukocytes, Male, Mice, Mice, Knockout, Neutrophils, Ovalbumin, Oxidation-Reduction, Receptors, Interleukin-8A, Receptors, Interleukin-8B, Respiratory Hypersensitivity, Respiratory Tract Diseases, Sulfonamides, T-Lymphocyte Subsets, 1107 Immunology, 1108 Medical Microbiology, 3101 Biochemistry and cell biology, 3105 Genetics, 3204 Immunology

Abstract:

RATIONALE: 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. OBJECTIVE: To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a significant neutrophilic component. FINDINGS: 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. CONCLUSION: 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.