title: The role of low-level lactate production in airway inflammation in asthma.
abstract: Warburg and coworkers (Warburg O, Posener K, Negelein E. Z Biochem 152: 319, 1924) first reported that cancerous cells switch glucose metabolism from oxidative phosphorylation to aerobic glycolysis, and that this switch is important for their proliferation. Nothing is known about aerobic glycolysis in T cells from asthma. The objective was to study aerobic glycolysis in human asthma and the role of this metabolic pathway in airway hyperreactivity and inflammation in a mouse model of asthma. Human peripheral blood and mouse spleen CD4 T cells were isolated by negative selection. T cell proliferation was measured by thymidine incorporation. Cytokines and serum lactate were measured by ELISA. Mouse airway hyperreactivity to inhaled methacholine was measured by a FlexiVent apparatus. The serum lactate concentration was significantly elevated in clinically stable asthmatic subjects compared with healthy and chronic obstructive pulmonary disease controls, and negatively correlated with forced expiratory volume in 1 s. Proliferating CD4 T cells from human asthma and a mouse model of asthma produced higher amounts of lactate upon stimulation, suggesting a heightened glycolytic activity. Lactate stimulated and inhibited T cell proliferation at low and high concentrations, respectively. Dichloroacetate (DCA), an inhibitor of aerobic glycolysis, inhibited lactate production, proliferation of T cells, and production of IL-5, IL-17, and IFN-γ, but it stimulated production of IL-10 and induction of Foxp3. DCA also inhibited airway inflammation and hyperreactivity in a mouse model of asthma. We conclude that aerobic glycolysis is increased in asthma, which promotes T cell activation. Inhibition of aerobic glycolysis blocks T cell activation and development of asthma.
authors.affiliation: National Jewish Health, Denver, CO 80206, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Ostroukhova
authors.forename: Nicholas
authors.initials: N
authors.lastname: Goplen
authors.forename: Md Zunayet
authors.initials: MZ
authors.lastname: Karim
authors.forename: Lidia
authors.initials: L
authors.lastname: Michalec
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Qiaoling
authors.initials: Q
authors.lastname: Liang
authors.forename: Rafeul
authors.initials: R
authors.lastname: Alam
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001249:Asthma / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D019344:Lactic Acid / Q000097:blood* / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases
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