Evaluation of Neutrophil Activation Status According to the Phenotypes of Adult Asthma

Abstract

Purpose Neutrophils are considered key effector cells in the pathogenic mechanisms of airway inflammation in asthma. This study assessed the activation status of neutrophils in adult asthmatics, and the therapeutic potential of FTY720, a synthetic sphingosine-1-phosphate analog, on activated neutrophils using an in vitro stimulation model. Methods We isolated peripheral blood neutrophils (PBNs) from 59 asthmatic patients (including 20 aspirin-exacerbated respiratory disease [AERD] and 39 aspirin-tolerant asthma [ATA] groups). PBNs were stimulated with N -formyl-methionyl-leucyl-phenylalanine (fMLP) or lipopolysaccharide (LPS) and their activation status was determined based on reactive oxygen species (ROS) production, cell surface expression of CD11b, interleukin (IL)-8 and matrix metallopeptidase (MMP)-9 release. PBNs were primed with FTY720 to evaluate its anti-inflammatory action. Results In vitro PBN stimulation with fMLP or LPS induced a significant increase in ROS/CD11b/IL-8/MMP-9 levels ( P < 0.05 for all). In asthmatics, fMLP-induced ROS level was significantly correlated with values of forced expiratory volume in 1 second/forced vital capacity (r = −0.278; P = 0.036), maximal mid-expiratory flow (r = −0.309; P = 0.019) and PC20 methacholine (r = −0.302; P = 0.029). In addition, ROS levels were significantly higher in patients with AERD and in those with severe asthma than in those with ATA or non-severe asthma ( P < 0.05 for all). FTY720 treatment could suppress ROS/CD11b levels, and LPS-induced IL-8 and MMP-9 levels ( P < 0.05 for all). Responders to FTY720 treatment had significantly higher neutrophil counts in sputum ( P = 0.004). Conclusions Our findings suggest a useful in vitro PBN stimulation model for evaluating the neutrophil functional status and the therapeutic potentials of neutrophil-targeting candidates in asthmatics.

Ceramide/sphingosine‐1‐phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma

“…bronchial hyper-reactivity to methacholine 36. In the present study, the expression of CD66 on peripheral neutrophils was correlated with ROS production from neutrophils, while peripheral and sputum neutrophil counts were not associated with ROS production from neutrophils.…”

Subphenotypes of nonsteroidal antiinflammatory disease‐exacerbated respiratory disease identified by latent class analysis

“…Neutrophils often represent the predominant inflammatory cells detected in the induced sputum obtained from patients with severely obstructed airways, experiencing uncontrolled symptoms and frequent exacerbations despite high intensity of treatment . Additionally, neutrophils generated more reactive oxygen species in patients with AERD and in those with severe asthma than in those with ATA or nonsevere asthma . In this study, all inflammatory patterns were seen in the NERD cohort.…”

An Alternative Dendritic Cell-Induced Murine Model of Asthma Exhibiting a Robust Th2/Th17-Skewed Response

“…Th17 cells, which mediate neutrophil recruitment, are associated with resistance to steroid therapy and severe clinical course of asthma. 37 Consequently, neutrophil infiltration is related with a severe disease phenotype in humans 3,38 and mice. 39 Patients with severe or steroid-resistant asthma show Th2 mixed with Th17 or Th1 immune responses.…”

“…1 Asthma has long been regarded as a T-helper (Th) 2-dependent, immunoglobulin (Ig) E-mediated disease. However, emerging evidence suggests that asthma is a complex disease displaying various endotypes: eosinophilic, neutrophilic, mixed eosinophilic/ neutrophilic, and paucigranulocytic 2,3 or Th2-predominant, Th2/Th17-predominant, and Th2/Th17-low asthma. 4,5 Approximately 358 million people suffer from asthma worldwide and its incidence continues to increase.…”