Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children. @ERSpublications Bronchial epithelium is a morphological and functional dysregulated gatekeeper in asthmatic children http://ow.ly/Y4MaM