Dataset Information

Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions.

ABSTRACT: A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN(-)) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN(-)). Airway epithelial cultures have been shown to secrete SCN(-) in a CFTR-dependent manner. Thus, reduced SCN(-) availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing the SCN(-) concentration in the nasal airway surface liquid (ASL) of CF patients and non-CF subjects and in the tracheobronchial ASL of CFTR-?F508 homozygous pigs and control littermates. In the nasal ASL, the SCN(-) concentration was ~30-fold higher than in serum independent of the CFTR mutation status of the human subject. In the tracheobronchial ASL of CF pigs, the SCN(-) concentration was somewhat reduced. Among human subjects, SCN(-) concentrations in the ASL varied from person to person independent of CFTR expression, and CF patients with high SCN(-) levels had better lung function than those with low SCN(-) levels. Thus, although CFTR can contribute to SCN(-) transport, it is not indispensable for the high SCN(-) concentration in ASL. The correlation between lung function and SCN(-) concentration in CF patients may reflect a beneficial role for SCN(-).

SUBMITTER: Lorentzen D

PROVIDER: S-EPMC3070840 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions.

Lorentzen Daniel D Durairaj Lakshmi L Pezzulo Alejandro A AA Nakano Yoko Y Launspach Janice J Stoltz David A DA Zamba Gideon G McCray Paul B PB Zabner Joseph J Welsh Michael J MJ Nauseef William M WM Bánfi Botond B

Free radical biology & medicine 20110218 9

A recently discovered enzyme system produces antibacterial hypothiocyanite (OSCN(-)) in the airway lumen by oxidizing the secreted precursor thiocyanate (SCN(-)). Airway epithelial cultures have been shown to secrete SCN(-) in a CFTR-dependent manner. Thus, reduced SCN(-) availability in the airway might contribute to the pathogenesis of cystic fibrosis (CF), a disease caused by mutations in the CFTR gene and characterized by an airway host defense defect. We tested this hypothesis by analyzing ...[more]

PMID: 21334431

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Project description:Interactions in the airway ecology of cystic fibrosis may alter organism persistence and clinical outcomes. Better understanding of such interactions could guide clinical decisions. We used generalized estimating equations to fit logistic regression models to longitudinal 2-year patient cohorts in the Cystic Fibrosis Foundation Patient Registry, 2003 to 2011, in order to study associations between the airway organisms present in each calendar year and their presence in the subsequent year. Models were adjusted for clinical characteristics and multiple observations per patient. Adjusted models were tested for sensitivity to cystic fibrosis-specific treatments. The study included 28,042 patients aged 6 years and older from 257 accredited U.S. care centers and affiliates. These patients had produced sputum specimens for at least two consecutive years that were cultured for methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, Stenotrophomonas maltophilia, Achromobacter xylosoxidans, and Candida and Aspergillus species. We analyzed 99.8% of 538,458 sputum cultures from the patients during the study period. Methicillin-sensitive S. aureus was negatively associated with subsequent Paeruginosa. Paeruginosa was negatively associated with subsequent B. cepacia complex, Axylosoxidans, and Smaltophilia. Bcepacia complex was negatively associated with the future presence of all bacteria studied, as well as with that of Aspergillus species. Paeruginosa, B. cepacia complex, and S. maltophilia were each reciprocally and positively associated with Aspergillus species. Independently of patient characteristics, the organisms studied interact and alter the outcomes of treatment decisions, sometimes in unexpected ways. By inhibiting P. aeruginosa, methicillin-sensitive S. aureus may delay lung disease progression. Paeruginosa and B. cepacia complex may inhibit other organisms by decreasing airway biodiversity, potentially worsening lung disease.

Project description:The microbial metagenome in cystic fibrosis (CF) airways was investigated by whole-genome shotgun sequencing of total DNA isolated from nasal lavage samples, oropharyngeal swabs, and induced sputum samples collected from 65 individuals with CF aged 7 to 50 years. Each patient harbored a personalized microbial metagenome unique in microbial load and composition, the exception being monocultures of the most common CF pathogens Staphylococcus aureus and Pseudomonas aeruginosa from patients with advanced lung disease. The sampling of the upper airways by nasal lavage uncovered the fungus Malassezia restricta and the bacterium Staphylococcus epidermidis as prominent species. Healthy and CF donors harbored qualitatively and quantitatively different spectra of commensal bacteria in their sputa, even in the absence of any typical CF pathogen. If P. aeruginosa, S. aureus, or Stenotrophomonas maltophilia belonged to the trio of the most abundant species in the CF sputum metagenome, common inhabitants of the respiratory tract of healthy subjects, i.e., Eubacterium sulci, Fusobacterium periodonticum, and Neisseria subflava, were present only in low numbers or not detectable. Random forest analysis identified the numerical ecological parameters of the bacterial community, such as Shannon and Simpson diversity, as the key parameters that globally distinguish sputum samples from CF and healthy donors. IMPORTANCE Cystic fibrosis (CF) is the most common life-limiting monogenetic disease in European populations and is caused by mutations in the CFTR gene. Chronic airway infections with opportunistic pathogens are the major morbidity that determines prognosis and quality of life in most people with CF. We examined the composition of the microbial communities of the oral cavity and upper and lower airways in CF patients across all age groups. From early on, the spectrum of commensals is different in health and CF. Later on, when the common CF pathogens take up residence in the lungs, we observed differential modes of depletion of the commensal microbiota in the presence of S. aureus, P. aeruginosa, S. maltophilia, or combinations thereof. It remains to be seen whether the implementation of lifelong CFTR (cystic fibrosis transmembrane conductance regulator) modulation will change the temporal evolution of the CF airway metagenome.

Dataset Information

Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions.

Publications

Concentration of the antibacterial precursor thiocyanate in cystic fibrosis airway secretions.

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