scholarly journals Cystic fibrosis–adaptedPseudomonas aeruginosaquorum sensinglasRmutants cause hyperinflammatory responses

2015 ◽  
Vol 1 (6) ◽  
pp. e1500199 ◽  
Author(s):  
Shantelle L. LaFayette ◽  
Daniel Houle ◽  
Trevor Beaudoin ◽  
Gabriella Wojewodka ◽  
Danuta Radzioch ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Opportunistic Pathogen ◽  
Respiratory Epithelial Cells ◽  
Adaptive Mutations ◽  
Cystic Fibrosis Lung Disease ◽  
Airway Infections ◽  
Respiratory Epithelial

Cystic fibrosis lung disease is characterized by chronic airway infections with the opportunistic pathogenPseudomonas aeruginosaand severe neutrophilic pulmonary inflammation.P. aeruginosaundergoes extensive genetic adaptation to the cystic fibrosis (CF) lung environment, and adaptive mutations in the quorum sensing regulator genelasRcommonly arise. We sought to define how mutations inlasRalter host-pathogen relationships. We demonstrate thatlasRmutants induce exaggerated host inflammatory responses in respiratory epithelial cells, with increased accumulation of proinflammatory cytokines and neutrophil recruitment due to the loss of bacterial protease–dependent cytokine degradation. In subacute pulmonary infections,lasRmutant–infected mice show greater neutrophilic inflammation and immunopathology compared with wild-type infections. Finally, we observed that CF patients infected withlasRmutants have increased plasma interleukin-8 (IL-8), a marker of inflammation. These findings suggest that bacterial adaptive changes may worsen pulmonary inflammation and directly contribute to the pathogenesis and progression of chronic lung disease in CF patients.

scholarly journals Defective organellar acidification as a cause of cystic fibrosis lung disease: reexamination of a recurring hypothesis

2009 ◽  
Vol 296 (6) ◽  
pp. L859-L867 ◽  
Author(s):  
Peter M. Haggie ◽  
A. S. Verkman
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Lung Disease ◽  
Alveolar Macrophages ◽  
Chloride Channels ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
Sodium Efflux ◽  
Cystic Fibrosis Lung Disease ◽  
Respiratory Epithelial

The cellular mechanisms by which loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel produce cystic fibrosis (CF) lung disease remain uncertain. Defective organellar function has been proposed as an important determinant in the pathogenesis of CF lung disease. According to one hypothesis, reduced CFTR chloride conductance in organelles in CF impairs their acidification by preventing chloride entry into the organelle lumen, which is needed to balance the positive charge produced by proton entry. According to a different hypothesis, CFTR mutation hyperacidifies organelles by an indirect mechanism involving unregulated sodium efflux through epithelial sodium channels. There are reports of defective Golgi, endosomal and lysosomal acidification in CF epithelial cells, defective phagolysosomal acidification in CF alveolar macrophages, and organellar hyperacidification in CF respiratory epithelial cells. The common theme relating too high or low organellar pH to cellular dysfunction and CF pathogenesis is impaired functioning of organellar enzymes, such as those involved in ceramide metabolism and protein processing in epithelial cells and antimicrobial activity in alveolar macrophages. We review here the evidence for defective organellar acidification in CF. Significant technical and conceptual concerns are discussed regarding the validity of data showing too high/low organellar pH in CF cells, and rigorous measurements of organellar pH in CF cells are reviewed that fail to support defective organellar acidification in CF. Indeed, there is an expanding body of evidence supporting the involvement of non-CFTR chloride channels in organellar acidification. We conclude that biologically significant involvement of CFTR in organellar acidification is unlikely.

scholarly journals The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease

2009 ◽  
Vol 297 (5) ◽  
pp. L828-L836 ◽  
Author(s):  
David P. Nichols ◽  
Assem G. Ziady ◽  
Samuel L. Shank ◽  
Jean F. Eastman ◽  
Pamela B. Davis
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Responses ◽  
Related Factor ◽  
Preclinical Models ◽  
Cytokines And Chemokines ◽  
Cystic Fibrosis Lung Disease ◽  
Culture Models ◽  
Multiple Cell ◽  
Anti Inflammatory

Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9( 11 )-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have significantly reduced airway inflammatory responses to both LPS and flagellin when treated with CDDO before inflammatory challenge. Anti-inflammatory effects observed include reduced airway neutrophilia, reduced concentrations of proinflammatory cytokines and chemokines, and reduced weight loss. Our findings with the synthetic triterpenoids in multiple cell culture models of CF human airway epithelia agree with effects previously described in other disease models (e.g., neoplastic cells). These include the ability to reduce NF-κB activation while increasing nuclear factor erythroid-related factor 2 (Nrf2) activity. As these two signaling pathways appear to be pivotal in regulating the net inflammatory response in the CF airway, these compounds are a promising potential anti-inflammatory therapy for CF lung disease.

X-Ray Microanalysis of Respiratory Epithelial Cells in the Study of Cystic Fibrosis

1990 ◽  
Vol 48 (2) ◽  
pp. 352-353
Author(s):  
Godfried M. Roomans ◽  
Samuel Sagström ◽  
Joke L.M. Ceulemans ◽  
Jan Bijman
Keyword(s):  
Cystic Fibrosis ◽  
Epithelial Cells ◽  
Water Transport ◽  
Clinical Symptoms ◽  
Chloride Secretion ◽  
Tracheal Mucosa ◽  
Respiratory Epithelial Cells ◽  
X Ray ◽  
Airway Infections ◽  
Respiratory Epithelial

One of the most important clinical symptoms associated with cystic fibrosis (CF) is obstructive airway disease and recurrent airway infections. The smaller airways in CF patients are blocked by viscous mucus, and infections are common and difficult to manage. Generally, lung disease is directly or indirectly the cause of death in CF. The viscous mucus in CF is likely to be a result of defective water transport in the respiratory epithelium. Water transport is coupled to chloride secretion, and it is strongly suspected that a defective chloride channel in the apical membrane of the respiratory epithelial cells is the basic error in CF. We therefore studied changes in the intracellular concentration of chloride (and other ions) by x-ray microanalysis of cultured respiratory epithelial cells under a variety of conditions.Tissues were obtained from material excised during polypectomy. The tracheal mucosa was digested with collagenase and the dispersed cells were plated onto Milliporefilters coated with human placental collagen.

scholarly journals Respiratory Epithelial Gene Expression in Patients with Mild and Severe Cystic Fibrosis Lung Disease

2006 ◽  
Vol 35 (3) ◽  
pp. 327-336 ◽  
Author(s):  
Jerry M. Wright ◽  
Christian A. Merlo ◽  
Jeffrey B. Reynolds ◽  
Pamela L. Zeitlin ◽  
Joe G. N. Garcia ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cystic Fibrosis ◽  
Lung Disease ◽  
Cystic Fibrosis Lung ◽  
Cystic Fibrosis Lung Disease ◽  
Respiratory Epithelial

scholarly journals Risk Factors for the Progression of Cystic Fibrosis Lung Disease throughout Childhood

2014 ◽  
Vol 11 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Don B. Sanders ◽  
Zhanhai Li ◽  
Anita Laxova ◽  
Michael J. Rock ◽  
Hara Levy ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cystic Fibrosis ◽  
Lung Disease ◽  
Cystic Fibrosis Lung ◽  
Cystic Fibrosis Lung Disease

scholarly journals Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease

Nature ◽  
2009 ◽  
Vol 458 (7241) ◽  
pp. 1039-1042 ◽  
Author(s):  
YuanYuan Gu ◽  
Isaac T. W. Harley ◽  
Lindsay B. Henderson ◽  
Bruce J. Aronow ◽  
Ilja Vietor ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Modifier Gene ◽  
Cystic Fibrosis Lung ◽  
Cystic Fibrosis Lung Disease

scholarly journals The lower airway microbiota in early cystic fibrosis lung disease: a longitudinal analysis

Thorax ◽  
2017 ◽  
Vol 72 (12) ◽  
pp. 1104-1112 ◽  
Author(s):  
Katherine B Frayman ◽  
David S Armstrong ◽  
Rosemary Carzino ◽  
Thomas W Ferkol ◽  
Keith Grimwood ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Longitudinal Analysis ◽  
Cystic Fibrosis Lung ◽  
Lower Airway ◽  
Cystic Fibrosis Lung Disease
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