Lentiviral vector gene therapy and CFTR modulators show comparable effectiveness in cystic fibrosis rat airway models.

Mutation-agnostic treatments such as airway gene therapy have the potential to treat any individual with cystic fibrosis (CF), irrespective of their CF transmembrane conductance regulator (CFTR) gene variants. The aim of this study was to employ two CF rat models, Phe508del and CFTR knockout (KO), to assess the comparative effectiveness of CFTR modulators and lentiviral (LV) vector-mediated gene therapy. Cells were isolated from the tracheas of rats and used to establish air-liquid interface (ALI) cultures.

An adapted novel flow cytometry methodology to delineate types of cell death in airway epithelial cells.

Current methodologies to measure apoptotic and necrotic cell death using flow cytometry do not adequately differentiate between the two. Here, we describe a flow cytometry methodology adapted to airway epithelial cells (AEC) to sufficiently differentiate apoptotic and necrotic AEC. Specifically, cell lines and primary AEC ( = 12) were permeabilized or infected with rhinovirus 1b (RV1b) over 48 h.

Ivacaftor or lumacaftor/ivacaftor treatment does not alter the core CF airway epithelial gene response to rhinovirus.

Background: Aberrant responses by the cystic fibrosis airway epithelium during viral infection may underly the clinical observations. Whether CFTR modulators affect antiviral responses by CF epithelia is presently unknown. We tested the hypothesis that treatment of CF epithelial cells with ivacaftor (Iva) or ivacaftor/lumacaftor (Iva/Lum) would improve control of rhinovirus infection.

Rhinovirus Infection Is Associated With Airway Epithelial Cell Necrosis and Inflammation via Interleukin-1 in Young Children With Cystic Fibrosis.

The responses of cystic fibrosis (CF) airway epithelial cells (AEC) to rhinovirus (RV) infection are likely to contribute to early pathobiology of lung disease with increased neutrophilic inflammation and lower apoptosis reported. Necrosis of AEC resulting in airway inflammation driven by IL-1 signaling is a characteristic finding in CF detectable in airways of young children. Being the most common early-life infection, RV-induced epithelial necrosis may contribute to early neutrophilic inflammation in CF via IL-1 signaling.

Aberrant cell migration contributes to defective airway epithelial repair in childhood wheeze.

Abnormal wound repair has been observed in the airway epithelium of patients with chronic respiratory diseases, including asthma. Therapies focusing on repairing vulnerable airways, particularly in early life, present a potentially novel treatment strategy. We report defective lower airway epithelial cell repair to strongly associate with common pre-school-aged and school-aged wheezing phenotypes, characterized by aberrant migration patterns and reduced integrin α5β1 expression.

Elastase Exocytosis by Airway Neutrophils Is Associated with Early Lung Damage in Children with Cystic Fibrosis.

Rationale: Neutrophils are recruited to the airways of individuals with cystic fibrosis (CF). In adolescents and adults with CF, airway neutrophils actively exocytose the primary granule protease elastase (NE), whose extracellular activity correlates with lung damage. During childhood, free extracellular NE activity is measurable only in a subset of patients, and the exocytic function of airway neutrophils is unknown.

Interleukin-1 is associated with inflammation and structural lung disease in young children with cystic fibrosis.

Background: Little is known about the role of interleukin (IL)-1 in the pathogenesis of cystic fibrosis (CF) lung disease. This study investigated the relationship between IL-1 signalling, neutrophilic inflammation and structural lung changes in children with CF.

Methods: Bronchoalveolar lavage fluid (BALf) from 102 children with CF were used to determine IL-1α, IL-1β, IL-8 levels and neutrophil elastase (NE) activity, which were then correlated to structural lung changes observed on chest computed tomography (CT) scans.

Airway surface liquid pH is not acidic in children with cystic fibrosis.

Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans.

Hypoxia and sterile inflammation in cystic fibrosis airways: mechanisms and potential therapies.

Cystic fibrosis is one of the most common autosomal recessive genetic diseases in Caucasian populations. Diagnosis via newborn screening and targeted nutritional and antibiotic therapy have improved outcomes, however respiratory failure remains the key cause of morbidity and mortality. Progressive respiratory disease in cystic fibrosis is characterised by chronic neutrophilic airway inflammation associated with structural airway damage leading to bronchiectasis and decreased lung function.