Cyanide levels found in infected cystic fibrosis sputum inhibit airway ciliary function

Abstract

We have previously reported cyanide at concentrations of up to 150 mM in the sputum of cystic fibrosis patients infected with Pseudomonas aeruginosa and a negative correlation with lung function. Our aim was to investigate possible mechanisms for this association, focusing on the effect of pathophysiologically relevant cyanide levels on human respiratory cell function.Ciliary beat frequency measurements were performed on nasal brushings and nasal air-liquid interface (ALI) cultures obtained from healthy volunteers and cystic fibrosis patients.Potassium cyanide decreased ciliary beat frequency in healthy nasal brushings (n56) after 60 min (150 mM: 47% fall, p,0.0012; 75 mM: 32% fall, p,0.0001). Samples from cystic fibrosis patients (n53) showed similar results (150 mM: 55% fall, p50.001). Ciliary beat frequency inhibition was not due to loss of cell viability and was reversible. The inhibitory mechanism was independent of ATP levels. KCN also significantly inhibited ciliary beat frequency in ALI cultures, albeit to a lesser extent. Ciliary beat frequency measurements on ALI cultures treated with culture supernatants from P. aeruginosa mutants defective in virulence factor production implicated cyanide as a key component inhibiting the ciliary beat frequency.If cyanide production similarly impairs mucocilliary clearance in vivo, it could explain the link with increased disease severity observed in cystic fibrosis patients with detectable cyanide in their airway. @ERSpublications Cyanide levels detectable in sputum inhibit ciliary function

Cyanide Toxicity to Burkholderia cenocepacia Is Modulated by Polymicrobial Communities and Environmental Factors

“…In the current study, we focused on expanding our in vitro understanding of competitive interactions mainly mediated by cyanide that was recently proposed to be an important strategy used by P. aeruginosa to kill B. multivorans in LB co-cultures (Smalley et al, 2015 ). HCN is a poison produced by P. aeruginosa in the CF lung that can affect host immune functions (Anderson et al, 2010 ; Lenney and Gilchrist, 2011 ; Nair et al, 2014 ), with also the potential to outcompete other bacterial species in polymicrobial infections and consequently reduce species diversity of these complex communities. However, we showed that the competitive efficacy of P. aeruginosa toward the Bcc via the release of toxins, including cyanide, depends on several factors such as the growth medium, the in vivo adaptive evolution of P. aeruginosa , and the presence of other bacteria in the mixed community.…”

Redox imaging and optical coherence tomography of the respiratory ciliated epithelium

“…12 Additionally, Pseudomonas aeruginosa, a bacterium that causes ventilator-associated pneumonia and can be found in the lungs of cystic fibrosis patients, excretes cyanide in the form of hydrogen cyanide. 13 Oxidative phosphorylation is the most efficient metabolic pathway to generate ATP. In ciliated epithelial cells, ATP powers the coordinated action of multiple dynein motor proteins that drive ciliary beating.…”

Paediatrics: messages from Munich

“…Recently, cyanide has been shown to impair mucociliary function in vitro [77]. G ilchrist et al [78] evaluated exhaled breath hydrogen cyanide (HCN) measured by SIFT (selected ion flow tube) mass spectrometry as a marker of P. aeruginosa infection in children.…”

“…edwards et al [127], in a large cross-sectional survey of all surviving preterm-born children in Wales (n=13 361) and matched term control children, confirmed previous findings that preterm birth increases the risk of wheezing disorders [128]. Both the <5-year-old and 5–10-year-old preterm born children in the RANOPS had higher reported rates of wheezing ever, wheeze in the last 3 months and use of inhaled medication than term infants.…”