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

Matheus Silverio Mattos,Laura Brandolini,Mauro Martins Teixeira,Cristiana Couto Garcia,Geovanni Dantas Cassali,Gabriel Augusto Oliveira Lopes,Lucas Kraemer,Fabricio Marcus Silva Oliveira,Marco Aurélio Martins,Maximiliano Ruben Ferrero,Diego Carlos Reis,Remo Castro Russo,Marcello Allegretti

doi:10.3389/fimmu.2020.566953

Abstract

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.

Highlights

Chemokines are small molecules from the cytokine family, which play a crucial physiological role in the biology of leukocytes and tissue resident cells [1]
Besides the early neutrophil influx into the airways after OVA challenge, there was an indication of pulmonary dysfunction marked by decreased lung volumes, attested by Total Lung Capacity (TLC), Residual Volume (RV), FRC, and FEV100 values (Figure 1D), with loss of pulmonary elasticity assessed by reduced compliance (Cdyn), increasing in lung resistance (Rl) and bronchial hyperreactivity evoked by methacholine (DRl) (Figure 1E)
These results indicated that neutrophils are among the first leukocytes to be recruited into the airways after a single OVA challenge during the Th2 mice asthma model, and this early neutrophilic infiltration is accompanied by altered bronchial reactivity in mice

Summary

Introduction

Chemokines are small molecules from the cytokine family, which play a crucial physiological role in the biology of leukocytes and tissue resident cells [1]. There is a growing body of evidence indicating that CXCR1 and CXCR2 may have a role in the pathogenesis of certain pulmonary diseases, including COPD, lung fibrosis and asthma [3]. The common point between these various diseases is the chronic presence of neutrophils in the lungs, generally associated with a high level of ELR+ chemokines and expression of CXCR1 and CXCR2 receptors. In this context, it is believed that CXCR1 and CXCR2 could be potential targets to restrain the immune response during respiratory allergies, pulmonary remodeling and scaring, lung infection, smoke exposure and inflammatory exacerbations [1]

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