glutaminase and Asthma

Topics: Ammonia; Animals; Anti-Inflammatory Agents; Asthma; Breath Tests; Case-Control Studies; Glutaminase; Glutamine; Humans; Hydrogen-Ion Concentration; Inflammation; Rats; Respiratory Mucosa; Steroids; Up-Regulation

Topics: Animals; Asthma; Benzopyrans; Cell Differentiation; Glutaminase; Mice; PPAR gamma; Th17 Cells

T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with

Topics: Adult; Alternaria; Animals; Asthma; Biomarkers; Blood Glucose; Bronchoalveolar Lavage Fluid; Case-Control Studies; Cells, Cultured; Dexamethasone; Disease Models, Animal; Drug Synergism; Female; Glucose Transporter Type 1; Glutaminase; Glutamine; Healthy Volunteers; Humans; Immunosuppressive Agents; Lung; Male; Mice; Middle Aged; Primary Cell Culture; Pyroglyphidae; Th17 Cells; Th2 Cells; Young Adult

Fluid condensed from the breath of patients with acute asthma is acidic. Several features of asthma pathophysiology can be initiated by exposure of the airway to acid. In renal tubular epithelium, glutaminase produces ammonia to buffer urinary acid excretion. We hypothesized that human airway epithelium could also express glutaminase. Here, we demonstrate that human airway epithelial cells in vitro have biochemical evidence for glutaminase activity and express mRNA for two glutaminase isoforms (KGA and GAC). Glutaminase activity increased in response to acidic stress (media pH 5.8) and was associated with both increased culture medium pH and improved cell survival. In contrast, activity was inhibited by interferon-gamma and tumor necrosis factor-alpha. Glutaminase protein was expressed in the human airway in vivo. Further, ammonia levels in the breath condensate of subjects with acute asthma were low (30 microM [range: 0-233], n = 18, age 23 +/- 2.5 yr) compared with control subjects (327 microM [14-1,220], n = 24, age 24 +/- 2.4 yr, p < 0.001), and correlated with condensate pH (r = 0.58, p < 0.001). These data demonstrate that glutaminase is expressed and active in the human airway epithelium and may be relevant both to the regulation of airway pH and to the pathophysiology of acute asthmatic airway inflammation.

Topics: Acute Disease; Adult; Ammonia; Analysis of Variance; Asthma; Biopsy; Blotting, Western; Breath Tests; Case-Control Studies; Cell Survival; Gene Expression Regulation; Glutaminase; Humans; Hydrogen-Ion Concentration; Immunohistochemistry; Inflammation; Interferon-gamma; Isomerism; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Necrosis Factor-alpha; Up-Regulation