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Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells.

ABSTRACT: Cystic fibrosis (CF) is a life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To gain an understanding of the epithelial dysfunction associated with CF mutations and discover biomarkers for therapeutics development, untargeted metabolomic analysis was performed on primary human airway epithelial cell cultures from three separate cohorts of CF patients and non-CF subjects. Statistical analysis revealed a set of reproducible and significant metabolic differences between the CF and non-CF cells. Aside from changes that were consistent with known CF effects, such as diminished cellular regulation against oxidative stress and osmotic stress, new observations on the cellular metabolism in the disease were generated. In the CF cells, the levels of various purine nucleotides, which may function to regulate cellular responses via purinergic signaling, were significantly decreased. Furthermore, CF cells exhibited reduced glucose metabolism in glycolysis, pentose phosphate pathway, and sorbitol pathway, which may further exacerbate oxidative stress and limit the epithelial cell response to environmental pressure. Taken together, these findings reveal novel metabolic abnormalities associated with the CF pathological process and identify a panel of potential biomarkers for therapeutic development using this model system.

SUBMITTER: Wetmore DR

PROVIDER: S-EPMC2945545 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells.

Wetmore Diana R DR Joseloff Elizabeth E Pilewski Joseph J Lee Douglas P DP Lawton Kay A KA Mitchell Matthew W MW Milburn Michael V MV Ryals John A JA Guo Lining L

The Journal of biological chemistry 20100730 40

Cystic fibrosis (CF) is a life-shortening disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. To gain an understanding of the epithelial dysfunction associated with CF mutations and discover biomarkers for therapeutics development, untargeted metabolomic analysis was performed on primary human airway epithelial cell cultures from three separate cohorts of CF patients and non-CF subjects. Statistical analysis revealed a set of reproducible and sign ...[more]

PMID: 20675369

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Project description:Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome.

Project description:IntroductionMetabolomics is an emerging area of research and has the potential to identify clinical biomarkers for predicting or diagnosing cystic fibrosis (CF) pulmonary exacerbations (PEx).ObjectiveTo identify clinically promising metabolites across different sample sources that can be used to predict or diagnose PEx in CF.Evidence reviewSearches for original literature were completed through EMBASE, MEDLINE, and all databases on the Web of Science with no restrictions on language or publication date. Gray literature was collected through Google Scholar. Additional studies were obtained by contacting authors and searching reference lists of candidate papers. The patient population included individuals with CF. Studies involving patients who underwent lung transplantation were excluded. The outcome was the prediction or diagnosis of pulmonary exacerbations from metabolites directly measured from biological samples. Search results were downloaded and imported into Covidence and duplicates were removed automatically. Any remaining duplicates were manually tagged and excluded. Two independent reviewers screened each abstract for eligibility and repeated this process for full texts. Risk of bias was conducted using QUADAS-2 by two independent reviewers. A third author resolved any remaining conflicts.ResultsA combined 3974 relevant abstracts were identified and 115 full texts were assessed for eligibility. The final 25 studies underwent data extraction for study design, patient demographics, studied metabolites, concentration values, and diagnostic accuracy values. Included studies differed considerably in methodologies, sample specimen types (exhaled breath condensate [EBC], sputum, saliva, plasma, urine), and disease states. We identified 19 unique metabolites that were measured by two or more studies of which 2 have the potential to predict PEx (EBC 4-hydroxycyclohexylcarboxylic acid [4-HCHC] and lactic acid) and 6 to diagnose PEx (EBC 4-HCHC and lactic acid, sputum lactic acid and nitrate, and plasma arginine and methionine).Conclusion and relevanceThis systematic review has identified promising metabolites for further study in CF. Certain metabolites may provide clinical potential in predicting or diagnosing PEx, but further validation studies are required. With better tools to aid in the earlier identification of PEx, clinicians can implement preventative measures to mitigate airway damage.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/.

Project description:Retained respiratory tract (RT) secretions, infection, and exuberant inflammatory responses are core abnormalities in cystic fibrosis (CF) lung disease. Factors contributing to the destructive CF airway inflammatory processes remain incompletely characterized. The pro-oxidative inflammatory CF RT milieu is known to contain enzymatically and nonenzymatically produced regulatory lipid mediators, a panel of structurally defined oxidized metabolites of polyunsaturated fatty acids known to play a role in pathology related to inflammation. Using an extraction protocol that maximizes recoveries of sputum-spiked deuterated standards, coupled with an LC/MS/MS detection system, this study presents a metabolomic method to assess a broad spectrum of regulatory lipid mediators in freshly obtained sputum from CF patients. A broad range of both proinflammatory and anti-inflammatory lipid mediators was detected, including PGE2, PGD2, TXB2, LTB4, 6-trans-LTB4, 20-OH-LTB4, 20-COOH-LTB4, 20-HETE, 15-HETE, 11-HETE, 12-HETE, 8-HETE, 9-HETE, 5-HETE, EpETrEs, diols, resolvin E1, 15-deoxy-PGJ2, and LXA4. The vast majority of these oxylipins have not been reported previously in CF RT secretions. Whereas direct associations of individual proinflammatory lipid mediators with compromised lung function (FEV-1) were observed, the relationships were not robust. However, multiple statistical analyses revealed that the regulatory lipid mediators profile taken in aggregate proved to have a stronger association with lung function in relatively stable outpatient adult CF patients. Our data reveal a relative paucity of the anti-inflammatory lipid mediator lipoxin A4 in CF sputum. Patients displaying detectable levels of the anti-inflammatory lipid mediator resolvin E1 demonstrated a better lung function compared to those patients with undetectable levels. Our data suggest that comprehensive metabolomic profiling of regulatory lipid mediators in CF sputum should contribute to a better understanding of the molecular mechanisms underlying CF RT inflammatory pathobiology. Further studies are required to determine the extent to which nutritional or pharmacological interventions alter the regulatory lipid mediators profile of the CF RT and the impact of potential modulations of RT regulatory lipid mediators on the clinical progression of CF lung disease.

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Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells.

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Metabolomic profiling reveals biochemical pathways and biomarkers associated with pathogenesis in cystic fibrosis cells.

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