Dataset Information

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

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.

SUBMITTER: Mattos MS

PROVIDER: S-EPMC7566412 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mattos Matheus Silverio MS Ferrero Maximiliano Ruben MR Kraemer Lucas L Lopes Gabriel Augusto Oliveira GAO Reis Diego Carlos DC Cassali Geovanni Dantas GD Oliveira Fabricio Marcus Silva FMS Brandolini Laura L Allegretti Marcello M Garcia Cristiana Couto CC Martins Marco Aurélio MA Teixeira Mauro Martins MM Russo Remo Castro RC

Frontiers in immunology 20201002

<h4>Rationale</h4>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.<h4>Objective</h4>To explore the role of Ladarixin, a dual CXCR1/2 antagonist, in several mouse models of airway inflammation with a signifi ...[more]

PMID: 33123138

Similar Datasets

Project description:BACKGROUND:Club Cell protein (CC)16 correlates with lung injury and respiratory complications, which are in part triggered by polymorphonuclear leukocytes (PMNL) in severely traumatized patients (TP). CC16 exerts anti-inflammatory and immunosuppressive effects, however, its influence on PMNL functions after trauma is unknown. Here, we evaluated whether CC16 present in sera from TP could modify the biological functions of PMNL. METHODS:Sera from 16 severely injured TP without pneumonia (no P, n =?8) or with pneumonia (P, n?=?8) were collected at admission to emergency department (ED) and 1 day prior pneumonia and pre-incubated with or without anti-CC16 antibody for CC16 neutralization. Samples from the equal post-injury days in the corresponding no P group were used. Neutrophils were isolated from healthy volunteers (HV, n =?5) and incubated with 20% of the serum medium from TP, respectively. In PMNL, CD62L, CD11b/CD18 and CD31 expression, migratory capacity, phagocytosis rate, oxidative burst and apoptosis were investigated. In isolated PMNL, CXCR1 and CXCR2 were neutralized before stimulation with CC16, and oxidative burst, phagocytosis and apoptosis were analyzed in neutrophils and their subsets. RESULTS:Serum from the P group enhanced significantly PMNL migration compared to no P group, while CC16-neutralization further increased the migratory rate of PMNL in both groups. CC16-neutralization increased significantly the expression of CD62L in the P group at ED. Oxidative burst was significantly increased in the P group vs. no P during the study period. CC16 seemed to have no influence on oxidative burst and phagocytosis in TP. However, in a more controlled study design, CC16 induced a significant increase of oxidative burst and a decrease of apoptosis of CD16+ granulocytes. These effects were markedly observed in mature CD16brightCD62Lbright and immune suppressive CD16brightCD62Ldim neutrophils. In mature subset, CXCR1 and CXCR2 neutralization diminished CC16-induced effects. CONCLUSIONS:CC16 in sera from multiply traumatized patients, notably of those with pneumonia, has significant effects on PMNL. The results suggest an association of CC16 with CXCR1 and CXCR2. Our data suggest that CC16 reduces the migratory capacity of PMNL and thus modulates their function in patients with respiratory complications after trauma.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets