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Changes in Metabolites Present in Lung-Lining Fluid Following Exposure of Humans to Ozone.

ABSTRACT: Controlled human exposure to the oxidant air pollutant ozone causes decrements in lung function and increased inflammation as evidenced by neutrophil influx into the lung and increased levels of proinflammatory cytokines in the airways. Here we describe a targeted metabolomics evaluation of human bronchoalveolar lavage fluid (BALF) following controlled in vivo exposure to ozone to gain greater insight into its pulmonary effects. In a 2-arm cross-over study, each healthy adult human volunteer was randomly exposed to filtered air (FA) and to 0.3 ppm ozone for 2 h while undergoing intermittent exercise with a minimum of 4 weeks between exposures. Bronchoscopy was performed and BALF obtained at 1 (n = 9) or 24 (n = 23) h postexposure. Metabolites were detected using ultrahigh performance liquid chromatography-tandem mass spectroscopy. At 1-h postexposure, a total of 28 metabolites were differentially expressed (DE) (p < .05) following ozone exposure compared with FA-exposure. These changes were associated with increased glycolysis and antioxidant responses, suggesting rapid increased energy utilization as part of the cellular response to oxidative stress. At 24-h postexposure, 41 metabolites were DE. Many of the changes were in amino acids and linked with enhanced proteolysis. Changes associated with increased lipid membrane turnover were also observed. These later-stage changes were consistent with ongoing repair of airway tissues. There were 1.37 times as many metabolites were differentially expressed at 24 h compared with 1-h postexposure. The changes at 1 h reflect responses to oxidative stress while the changes at 24 h indicate a broader set of responses consistent with tissue repair. These results illustrate the ability of metabolomic analysis to identify mechanistic features of ozone toxicity and aspects of the subsequent tissue response.

SUBMITTER: Cheng W

PROVIDER: S-EPMC6348881 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Changes in Metabolites Present in Lung-Lining Fluid Following Exposure of Humans to Ozone.

Cheng WanYun W Duncan Kelly E KE Ghio Andrew J AJ Ward-Caviness Cavin C Karoly Edward D ED Diaz-Sanchez David D Conolly Rory B RB Devlin Robert B RB

Toxicological sciences : an official journal of the Society of Toxicology 20180601 2

Controlled human exposure to the oxidant air pollutant ozone causes decrements in lung function and increased inflammation as evidenced by neutrophil influx into the lung and increased levels of proinflammatory cytokines in the airways. Here we describe a targeted metabolomics evaluation of human bronchoalveolar lavage fluid (BALF) following controlled in vivo exposure to ozone to gain greater insight into its pulmonary effects. In a 2-arm cross-over study, each healthy adult human volunteer was ...[more]

PMID: 29471466

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Project description:RationaleAir pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism.ObjectivesTo examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers.MethodsSerum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach.Measurements and main resultsMetabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial β-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of β-oxidation by ozone in exercising humans.ConclusionsAs in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517).

Project description:BackgroundHyperresponsiveness to inhaled non-infectious microbial particles (NIMPs) has been associated with illnesses in the airways. Hypersensitivity pneumonitis (HP) is considered to be the prototype for these NIMPs-related diseases; however, there is no consensus on the definitions or diagnostic criteria for HP and the spectrum of related illnesses.Methods and findingsIn order to identify the possible diagnostic markers for illnesses associated with NIMPs in alveolar lining fluid, we performed a proteomic analysis using a two-dimensional difference gel electrophoresis on bronchoalveolar lavage (BAL) fluid from patients with exposure to NIMPs in the context of damp building-related illness (DBRI) or conditions on the borderline to acute HP, designated here as agricultural type of microbial exposure (AME). Samples from patients with HP and sarcoidosis (SARC) were included for reference. Results were compared to results of healthy subjects (CTR). Western blot was used for validation of potential marker proteins from BAL fluid and plasma. Protein expression patterns suggest a close similarity between AME and HP, while DBRI was similar to CTR. However, in DBRI the levels of the inflammation associated molecules galectin-3 and alpha-1-antitrypsin were increased. A novel finding emerging from this study was the increases of semenogelin levels in BAL fluid from patients with AME, HP and SARC. Histone 4 levels were increased in AME, HP and SARC. Elevated plasma levels of histone 2B were detected in HP and SARC, suggesting it to be a potential blood indicator for inflammatory diseases of the lungs.ConclusionsIn this study, the proteomic changes in bronchoalveolar lavage of DBRI patients were distinct from other NIMP exposure associated lung diseases, while changes in AME overlapped those observed for HP patient samples. Some of the proteins identified in this study, semenogelin and histone 4, could function as diagnostic markers for differential diagnosis between DBRI and HP-like conditions.

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Changes in Metabolites Present in Lung-Lining Fluid Following Exposure of Humans to Ozone.

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Changes in Metabolites Present in Lung-Lining Fluid Following Exposure of Humans to Ozone.

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