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

  • Front Immunol. 2020 Oct 2;11:566953. doi: 10.3389/fimmu.2020.566953.
Matheus Silverio Mattos  1 ,  Maximiliano Ruben Ferrero  2 ,  Lucas Kraemer  1 ,  Gabriel Augusto Oliveira Lopes  1 ,  Diego Carlos Reis  3 ,  Geovanni Dantas Cassali  3 ,  Fabricio Marcus Silva Oliveira  3 ,  Laura Brandolini  4 ,  Marcello Allegretti  4 ,  Cristiana Couto Garcia  5 ,  Marco Aurélio Martins  2 ,  Mauro Martins Teixeira  6 ,  Remo Castro Russo  1  6
Affiliations
  • 1. Laboratory of Comparative Pathology, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • 2. Laboratory of Inflammation, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil.
  • 3. Laboratory of Comparative Pathology, Department of General Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
  • 4. R&D Department, Dompé Farmaceutici S.p.a., L'Aquila, Italy.
  • 5. Laboratory of Respiratory Virus and Measles, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro, Brazil.
  • 6. Laboratory of Immunopharmacology, Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
PMID: 33123138 DOI: 10.3389/fimmu.2020.566953
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.

Keywords
asthma; chronic obstructive pulmonary disease; fibrosis; influenza A (H1N1); neutrophils (PMNs).
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