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NOX4 expression linked to ciliary dysfunction in asthma patients

Researchers observed a correlation between NOX4 expression and reactive oxygen species generation in bronchial epithelial cells taken from asthmatic patients, which increased the risk for ciliary dysfunction, according to data recently published in Chest.

Further, researchers noted the risk can be mitigated through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, according to the abstract.

“Bronchial epithelial cells from asthmatic subjects with neutrophilic airway inflammation have heightened NOX4 expression and [reactive oxygen species] generation. NADPH oxidase inhibition in an in vivo murine model of asthma improved ciliary function, which was also confirmed in ex vivo bronchial epithelial cells from subjects with neutrophilic asthma,” Wing-Yan Heidi Wan, PhD, of the Institute for Lung Health and the department of infection, immunity & inflammation at Glenfield Hospital in the University of Leicester, U.K., and colleagues wrote. “These findings support the view that NADPH oxidase inhibition and in particular NOX4 might present a new stratified approach for the treatment of neutrophilic asthma.”

Wan and colleagues used video-microscopy on fresh ex vivo epithelial strip samples from asthmatic patients to determine bronchial epithelial ciliary function, according to the abstract. Damage to bronchial epithelial oxidation was determined by expression of 8-oxo-dG, whereas expression of nitrogen oxides/dual oxidase (NOX/DUOX) was determined through microarrays and DUOX1 and DUOX2 expression was assessed in bronchial biopsies. After NADPH oxidation, ciliary dysfunction was determined using GKT137831 in fresh epithelial strips as well as murine model of ovalbumin sensitization.

The researchers found ciliary beat frequency was impaired in 11 samples with sputum neutrophilia compared with 10 samples without sputum neutrophilia (5.8 vs. 8.8; P = .003), and this result was correlated with sputum neutrophil count (r = –0.70; P < .001), according to the abstract. There were expressions of DUOX1, DUOX2 and NOX4 in primary bronchial epithelial cells; in both asthmatic samples with neutrophils and without neutrophils, DUOX1 was elevated, whereas DUOX2 was elevated in samples without neutrophils in vivo.

There was no persistence of ciliary dysfunction in primary epithelial cultures; however, Wan and colleagues noted increased NOX4 and reactive oxygen species generation among samples with neutrophilic asthma. Use of GKT137831 was associated with improvement in ciliary function relative to the intensity of neutrophilic inflammation in 13 ex vivo epithelial strips and also the elimination of ciliary dysfunction in murine models of asthma. – by Jeff Craven

Disclosure: Wan reports no relevant financial disclosures. Several researchers report employment, ownership and advisory board roles with, as well as research support and other honoraria from Aerovance, AstraZeneca, Genkyotex SA, GlaxoSmithKline, MedImmune, Novartis, Pfizer and Roche. Please see the full study for all researchers’ relevant financial disclosures.