scholarly journals Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

2016 ◽  
Vol 48 (6) ◽  
pp. 1612-1621 ◽  
Author(s):  
Charles R. Esther ◽  
Lidija Turkovic ◽  
Tim Rosenow ◽  
Marianne S. Muhlebach ◽  
Richard C. Boucher ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Small Peptides ◽  
Neutrophilic Inflammation ◽  
Cellular Energy ◽  
Cystic Fibrosis Lung Disease ◽  
And Oxidative Stress

Neutrophilic airway inflammation plays a role in early structural lung disease in cystic fibrosis, but the mechanisms underlying this pathway are incompletely understood.Metabolites associated with neutrophilic inflammation were identified by discovery metabolomics on bronchoalveolar lavage fluid supernatant from 20 preschool children (2.9±1.3 years) with cystic fibrosis. Targeted mass-spectrometric detection of relevant metabolites was then applied to 34 children (3.5±1.5 years) enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) who underwent chest computed tomography and bronchoalveolar lavage from two separate lobes during 42 visits. Relationships between metabolites and localised structural lung disease were assessed using multivariate analyses.Discovery metabolomics identified 93 metabolites associated with neutrophilic inflammation, including pathways involved in metabolism of adenyl purines, amino acids and small peptides, cellular energy and lipids. In targeted mass spectrometry, products of adenosine metabolism, protein catabolism and oxidative stress were associated with structural lung disease and predicted future bronchiectasis, and activities of enzymes associated with adenosine metabolism were elevated in the samples with early disease.Metabolomics analyses revealed metabolites and pathways altered with neutrophilic inflammation and destructive lung disease. These pathways can serve as biomarkers and potential therapeutic targets for early cystic fibrosis lung disease.

scholarly journals Mucus accumulation in the lungs precedes structural changes and infection in children with cystic fibrosis

2019 ◽  
Vol 11 (486) ◽  
pp. eaav3488 ◽  
Author(s):  
Charles R. Esther ◽  
Marianne S. Muhlebach ◽  
Camille Ehre ◽  
David B. Hill ◽  
Matthew C. Wolfgang ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Inflammatory Markers ◽  
Structural Changes ◽  
Bronchoalveolar Lavage Fluid ◽  
Airway Disease ◽  
Lavage Fluid ◽  
Preventive Therapy ◽  
Molecular Analyses ◽  
And Oxidative Stress

Although destructive airway disease is evident in young children with cystic fibrosis (CF), little is known about the nature of the early CF lung environment triggering the disease. To elucidate early CF pulmonary pathophysiology, we performed mucus, inflammation, metabolomic, and microbiome analyses on bronchoalveolar lavage fluid (BALF) from 46 preschool children with CF enrolled in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST CF) program and 16 non-CF disease controls. Total airway mucins were elevated in CF compared to non-CF BALF irrespective of infection, and higher densities of mucus flakes containing mucin 5B and mucin 5AC were observed in samples from CF patients. Total mucins and mucus flakes correlated with inflammation, hypoxia, and oxidative stress. Many CF BALFs appeared sterile by culture and molecular analyses, whereas other samples exhibiting bacterial taxa associated with the oral cavity. Children without computed tomography–defined structural lung disease exhibited elevated BALF mucus flakes and neutrophils, but little/no bacterial infection. Although CF mucus flakes appeared “permanent” because they did not dissolve in dilute BALF matrix, they could be solubilized by a previously unidentified reducing agent (P2062), but notN-acetylcysteine or deoxyribonuclease. These findings indicate that early CF lung disease is characterized by an increased mucus burden and inflammatory markers without infection or structural lung disease and suggest that mucolytic and anti-inflammatory agents should be explored as preventive therapy.

scholarly journals 2045 The role of TGFβ in driving early cystic fibrosis lung disease

2018 ◽  
Vol 2 (S1) ◽  
pp. 33-33
Author(s):  
Elizabeth L. Kramer ◽  
William Hardie ◽  
Kristin Hudock ◽  
Cynthia Davidson ◽  
Alicia Ostmann ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Bronchoalveolar Lavage Fluid ◽  
Transforming Growth Factor ◽  
Genetic Modifier ◽  
Lavage Fluid ◽  
Lung Mechanics ◽  
Patient Specific

OBJECTIVES/SPECIFIC AIMS: Transforming growth factor-beta (TGFβ) is a genetic modifier of cystic fibrosis (CF) lung disease. TGFβ’s pulmonary levels in young CF patients and its mechanism of action in CF are unknown. We examined TGFβ levels in children with CF and investigated responses of human airway epithelial cells (AECs) and mice to TGFβ. METHODS/STUDY POPULATION: TGFβ levels in bronchoalveolar lavage fluid from CF patients (n=15) and non-CF control patients (n=21)<6 years old were determined by ELISA. CF mice and non-CF mice were intratracheally treated with an adenoviral TGFβ1 vector or PBS; lungs were collected for analysis at day 7. Human CF and non-CF AECs were treated with TGFβ or PBS for 24 hours then collected for analysis. RESULTS/ANTICIPATED RESULTS: Young CF patients had higher bronchoalveolar lavage fluid TGFβ than non-CF controls (p=0.03). Mouse lungs exposed to TGFβ demonstrated inflammation, goblet cell hyperplasia, and decreased CFTR expression. CF mice had greater TGFβ-induced lung mechanics abnormalities than controls; both CF human AECs and CF mice showed higher TGFβ induced MAPK and PI3K signaling compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: For the first time, we show increased TGFβ levels very early in CF. TGFβ drives CF lung abnormalities in mouse and human models; CF models are more sensitive to TGFβ’s effects. Understanding the role of TGFβ in promoting CF lung disease is critical to developing patient specific treatments.

scholarly journals Novel Neutrophil-Derived Proteins in Bronchoalveolar Lavage Fluid Indicate an Exaggerated Inflammatory Response in Pediatric Cystic Fibrosis Patients

2007 ◽  
Vol 53 (10) ◽  
pp. 1782-1791 ◽  
Author(s):  
Brendan J McMorran ◽  
Severine A Ouvry Patat ◽  
John B Carlin ◽  
Keith Grimwood ◽  
Alun Jones ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Inflammatory Response ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Airway Inflammation ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Respiratory Pathogens ◽  
Tissue Destruction ◽  
Tof Ms

Abstract Background: Airway inflammation in cystic fibrosis (CF) is exaggerated and characterized by neutrophil-mediated tissue destruction, but its genesis and mechanisms remain poorly understood. To further define the pulmonary inflammatory response, we conducted a proteome-based screen of bronchoalveolar lavage fluid (BALF) collected from young children with and without CF experiencing endobronchial infection. Methods: We collected BALF samples from 45 children younger than 5 years and grouped them according to the presence of respiratory pathogens: ≥1 × 105 colony-forming units (CFU)/mL BALF (18 and 12 samples with and without CF, respectively) and &lt;1 × 105 CFU/mL (23 and 15 samples). BALF proteins were analyzed with SELDI-TOF mass spectrometry (MS) and H4 ProteinChips®. Proteins were identified and characterized using trypsin digestion, tandem MS, Fourier transform ion cyclotron resonance MS, immunoblotting, and ELISA. Results: The SELDI-TOF MS BALF profiles contained 53 unique, reliably detected proteins. Peak intensities of 24 proteins differed significantly between the CF and non-CF samples. They included the neutrophil proteins, α-defensin 1 and 2, S100A8, S100A9, and S100A12, as well as novel forms of S100A8 and S100A12 with equivalent C-terminal deletions. Peak intensities of these neutrophil proteins and immunoreactive concentrations of selected examples were significantly higher in CF than non-CF samples. Conclusions: Small neutrophil-derived BALF proteins, including novel C-terminal truncated forms of S100A proteins, are easily detected with SELDI-TOF MS. Concentrations of these molecules are abnormally high in early CF lung disease. The data provide new insights into CF lung disease and identify novel proteins strongly associated with CF airway inflammation.

scholarly journals Metabolomic analysis of bronchoalveolar lavage fluid from cystic fibrosis patients

Biomarkers ◽  
2009 ◽  
Vol 14 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Justyna E. Wolak ◽  
Charles R. Esther ◽  
Thomas M. O’Connell
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Metabolomic Analysis

scholarly journals Degradation of Annexin I in Bronchoalveolar Lavage Fluid from Patients with Cystic Fibrosis

1998 ◽  
Vol 18 (1) ◽  
pp. 120-128 ◽  
Author(s):  
Francis H. C. Tsao ◽  
Keith C. Meyer ◽  
Xiaoming Chen ◽  
Nancy S. Rosenthal ◽  
Junpei Hu
Keyword(s):  
Cystic Fibrosis ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Annexin I
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