Abstract
Neutrophils (PMNs) contain and release a powerful arsenal of mediators, including several granular enzymes, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). Although airway neutrophilia is associated with severity, poor response to glucocorticoids and exacerbations, the pathophysiological role of neutrophils in asthma remains poorly understood. Twenty-four patients with asthma and 22 healthy controls (HCs) were prospectively recruited. Highly purified peripheral blood neutrophils (> 99%) were evaluated for ROS production and activation status upon stimulation with lipopolysaccharide (LPS), N-formylmethionyl-leucyl-phenylalanine (fMLP) and phorbol 12-myristate 13-acetate (PMA). Plasma levels of myeloperoxidase (MPO), CXCL8, matrix metalloproteinase-9 (MMP-9), granulocyte–monocyte colony-stimulating factor (GM-CSF) and vascular endothelial growth factor (VEGF-A) were measured by ELISA. Plasma concentrations of citrullinated histone H3 (CitH3) and circulating free DNA (dsDNA) were evaluated as NET biomarkers. Activated PMNs from asthmatics displayed reduced ROS production and activation status compared to HCs. Plasma levels of MPO, MMP-9 and CXCL8 were increased in asthmatics compared to HCs. CitH3 and dsDNA plasma levels were increased in asthmatics compared to controls and the CitH3 concentrations were inversely correlated to the % decrease in FEV1/FVC in asthmatics. These findings indicate that neutrophils and their mediators could have an active role in asthma pathophysiology.
Highlights
Bronchial asthma is a heterogeneous chronic inflammatory disease with a broad spectrum of severity [1]
We evaluated the plasma levels of different components of Highly purified neutrophils isolated from peripheral blood of asthma patients and healthy donors produced reactive oxygen species (ROS) in response to two agonists (LPS and fMLP) that activate specific receptors (TLR4 and FPR, respectively) expressed on the cytoplasmic membrane of these cells [24, 66]
The mobilization of two surface markers of neutrophils, CD11b and CD62L, induced by LPS and fMLP, were more marked in cells from healthy donors compared to asthmatics
Summary
Bronchial asthma is a heterogeneous chronic inflammatory disease with a broad spectrum of severity [1]. Asthma heterogeneity mirrors the underlying molecular mechanisms and contributes to the variable presentation of the disease [4]. T2-high asthma is the most frequent endo/phenotype and is canonically marked by activation of type 2 helper (Th2) cells, type 2 innate lymphoid cells (ILC2s), mast cells, basophils, eosinophils and the production of type 2 cytokines (e.g., IL-3, IL-4, IL-5 and IL-13) [8,9,10]. Besides T H2 cells, T follicular helper ( TFH) cells, a specialized subset of C XCR5+ CD4+ T cells, are a major source of IL-4 and IL-21 [11], closely regulating IgE isotype switching during asthma
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