Interleukin-18, IL-18 binding protein and IL-18 receptor expression in asthma: a hypothesis showing IL-18 promotes epithelial cell differentiation.

Objective: In asthma, genome-wide association studies have shown that interleukin-18 (IL-18) receptor 1 gene () and sputum IL-18 are increased during exacerbations. However, the role of the IL-18 axis in bronchial epithelial function is unclear. To investigate IL-18, IL-18 binding protein (BP) and IL-18R expression in bronchial biopsies and sputum samples from patients with asthma, and to determine its functional role using bronchial epithelial cells.

Fibrocyte localisation to the ASM bundle in asthma: bidirectional effects on cell phenotype and behaviour.

Objectives: Airway hyper-responsiveness and persistent airflow obstruction contribute to asthma pathogenesis and symptoms, due in part to airway smooth muscle (ASM) hypercontractility and increased ASM mass. Fibrocytes have been shown to localise to the ASM in asthma however it is not known whether fibrocytes localise to the ASM in nonasthmatic eosinophilic bronchitis (NAEB) and chronic obstructive pulmonary disease (COPD). In addition, the potential consequences of fibrocyte localisation to ASM as regards asthma pathophysiology has not been widely studied.

ST2 expression and release by the bronchial epithelium is downregulated in asthma.

Background: The airway epithelium plays an important role in wound repair, host defense and is involved in the immunopathogenesis of asthma. Genome wide association studies have described associations between ST2/Interleukin (IL)-33 genes in asthma, but its role in bronchial epithelium is unclear.

Methods: ST2 expression was examined in subjects with asthma and healthy controls in bronchial epithelium from biopsies (n = 27 versus n = 9) and brushings (n = 34 versus n = 20) by immunohistochemistry and RNA-Seq.

Validation of antibodies for the specific detection of human TRPA1.

The transient receptor potential cation channel family member ankyrin 1 (TRPA1) is a potential target for several diseases, but detection of human TRPA1 (hTRPA1) protein in cells and tissues is problematic as rigorous antibody validation is lacking. We expressed hTRPA1 in a TRPA1-negative cell line to evaluate 5 commercially available antibodies by western blotting, immunofluorescence, immunocytochemistry and flow cytometry. The three most cited anti-TRPA1 antibodies lacked sensitivity and/or specificity, but two mouse monoclonal anti-TRPA1 antibodies detected hTRPA1 specifically in the above assays.

Sputum is reduced in COPD following treatment with benralizumab.

We hypothesized whether the reduction in eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) following treatment with benralizumab, a humanized, afucosylated, monoclonal antibody that binds to interleukin-5 receptor α, increases the airway bacterial load. Analysis of sputum samples of COPD patients participating in a Phase II trial of benralizumab indicated that sputum 16S rDNA load and were reduced following treatment with benralizumab. However, in vitro, eosinophils did not affect the killing of the common airway pathogens or .

DP antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D type 2 receptor (DP) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP in airway smooth muscle cells.

Increased β2-adrenoceptor phosphorylation in airway smooth muscle in severe asthma: possible role of mast cell-derived growth factors.

The purpose of this study was to investigate whether growth factors produced by activated human lung mast cells (HLMCs) impair β -adrenoceptor (β -AR) function in human airway smooth muscle (ASM) cells. Protein array analysis confirmed the presence of various growth factors, including transforming growth factor (TGF)-β1, in the supernatants of high-affinity IgE receptor (FcεRI)-activated HLMCs which, when applied to ASM cells, impaired albuterol-induced cyclic adenosine monophosphate (cAMP) production, an effect that was prevented following neutralization of TGF-β1. This blunted β -AR response was reproduced by treating ASM cells with TGF-β1 or fibroblast growth factor (FGF)-2, which induced β -AR phosphorylation at tyrosine residues Tyr and Tyr , and significantly reduced the maximal bronchorelaxant responses to isoproterenol in human precision cut lung slices (PCLS).

Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

Background: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling.

, and study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss.

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70°C) for 10 s to mimic thermoplasty.

Protein phosphatase 5 mediates corticosteroid insensitivity in airway smooth muscle in patients with severe asthma.

Background: The mechanisms driving glucocorticoid (GC) insensitivity in patients with severe asthma are still unknown. Recent evidence suggests the existence of GC-insensitive pathways in airway smooth muscle (ASM) caused by a defect in GC receptor (GRα) function. We examined whether other mechanisms could potentially explain the reduced sensitivity of ASM cells to GC in severe asthmatics.

NADPH Oxidase-4 Overexpression Is Associated With Epithelial Ciliary Dysfunction in Neutrophilic Asthma.

Background: Bronchial epithelial ciliary dysfunction is an important feature of asthma. We sought to determine the role in asthma of neutrophilic inflammation and nicotinamide adenine dinucleotide phosphate (NADPH) oxidases in ciliary dysfunction.

Methods: Bronchial epithelial ciliary function was assessed by using video microscopy in fresh ex vivo epithelial strips from patients with asthma stratified according to their sputum cell differentials and in culture specimens from healthy control subjects and patients with asthma.

Bidirectional Counterregulation of Human Lung Mast Cell and Airway Smooth Muscle β2 Adrenoceptors.

Human lung mast cells (HLMCs) play a central role in asthma pathogenesis through their relocation to the airway smooth muscle (ASM) bundles. β2 adrenoceptor (β2-AR)-agonists are used to relieve bronchoconstriction in asthma, but may reduce asthma control, particularly when used as monotherapy. We hypothesized that HLMC and human ASM cell (HASMC) responsiveness to β2-AR agonists would be attenuated when HLMCs are in contact with HASMCs.

Abnormal corticosteroid signalling in airway smooth muscle: mechanisms and perspectives for the treatment of severe asthma.

Growing in vivo evidence supports the concept that airway smooth muscle produces various immunomodulatory factors that could contribute to asthma pathogenesis via the regulation of airway inflammation, airway narrowing and remodelling. Targeting ASM using bronchial thermoplasty has provided undeniable clinical benefits for patients with uncontrolled severe asthma who are refractory to glucocorticoid therapy. The present review will explain why the failure of glucocorticoids to adequately manage patients with severe asthma could derive from their inability to affect the immunomodulatory potential of ASM.

Effect of the plant derivative Compound A on the production of corticosteroid-resistant chemokines in airway smooth muscle cells.

Preclinical models of human conditions including asthma showed the therapeutic potential of Compound A (CpdA), a dissociated glucocorticoid (GC) receptor (GRα) ligand. Whether CpdA inhibits GC resistance, a central feature of severe asthma, has not been addressed. We investigated whether CpdA modulates cytokine-induced GC resistance in human airway smooth muscle (ASM) cells.

Mechanisms of glucocorticoid action and insensitivity in airways disease.

Glucocorticoids are the mainstay for the treatment of chronic inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD). However, it has been recognized that glucocorticoids do not work well in certain patient populations suggesting reduced sensitivity. The ultimate biologic responses to glucocorticoids are determined by not only the concentration of glucocorticoids but also the differences between individuals in glucocorticoid sensitivity, which is influenced by multiple factors.

Functional KCa3.1 channels regulate steroid insensitivity in bronchial smooth muscle cells.

Identifying the factors responsible for relative glucocorticosteroid (GC) resistance present in patients with severe asthma and finding tools to reverse it are of paramount importance. In asthma we see in vivo evidence of GC-resistant pathways in airway smooth muscle (ASM) bundles that can be modeled in vitro by exposing cultured ASM cells to TNF-α/IFN-γ. This action drives GC insensitivity via protein phosphatase 5-dependent impairment of GC receptor phosphorylation.

Counterregulation of beta(2)-adrenoceptor function in human mast cells by stem cell factor.

Background: Mast cells contribute to the pathophysiology of asthma with the sustained release of both preformed and newly generated mediators in response to allergens and other diverse stimuli. Stem cell factor (SCF) is the key human mast cell growth factor, but also primes mast cells for mediator release. SCF expression is markedly increased in asthmatic airways.