دورية أكاديمية
أعرض في EDS

15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.

التفاصيل البيبلوغرافية
العنوان: 15LO1 dictates glutathione redox changes in asthmatic airway epithelium to worsen type 2 inflammation.
المؤلفون: Nagasaki T; Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Schuyler AJ; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Zhao J; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; University of Pittsburgh Asthma and Environmental Lung Health Institute, Pittsburgh, Pennsylvania, USA., Samovich SN; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Yamada K; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Deng Y; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Ginebaugh SP; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.; Department of Medicine and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Christenson SA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCSF, San Francisco, California, USA., Woodruff PG; Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCSF, San Francisco, California, USA., Fahy JV; Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCSF, San Francisco, California, USA., Trudeau JB; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Stoyanovsky D; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Ray A; University of Pittsburgh Asthma and Environmental Lung Health Institute, Pittsburgh, Pennsylvania, USA.; Department of Medicine and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Tyurina YY; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Kagan VE; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Wenzel SE; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; University of Pittsburgh Asthma and Environmental Lung Health Institute, Pittsburgh, Pennsylvania, USA.
المصدر: The Journal of clinical investigation [J Clin Invest] 2022 Jan 04; Vol. 132 (1).
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: Ferroptosis* , Signal Transduction*, Arachidonate 15-Lipoxygenase/*metabolism , Asthma/*enzymology , Epithelial Cells/*enzymology , Glutathione/*metabolism , Respiratory Mucosa/*enzymology, Cell Line ; Epithelial Cells/pathology ; Gene Expression Regulation ; Humans ; Inflammation/enzymology ; Inflammation/pathology ; Oxidation-Reduction ; Respiratory Mucosa/pathology
مستخلص: Altered redox biology challenges all cells, with compensatory responses often determining a cell's fate. When 15 lipoxygenase 1 (15LO1), a lipid-peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine-binding protein 1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase 4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter SLC7A11 critically restores/maintains intracellular GSH. We hypothesized that high 15LO1, PEBP1, and GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG) ratios, to enhance type 2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11, and T2 biomarkers (Western blot and RNA-Seq) were measured in asthmatic and healthy control (HC) cells and fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared with HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, a T2 cytokine (IL-13) induced 15LO1 generation of hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers, and worsened clinical outcomes. Thus, 15LO1 pathway-induced redox biology perturbations worsen T2 inflammation and asthma control, supporting 15LO1 as a therapeutic target.
التعليقات: Comment in: J Clin Invest. 2022 Jan 4;132(1):. (PMID: 34981786)
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معلومات مُعتمدة: P01 AI106684 United States AI NIAID NIH HHS; R01 AI145406 United States AI NIAID NIH HHS; U10 HL109152 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: Asthma; Metabolism; Pulmonology; Radicals; Th2 response
المشرفين على المادة: EC 1.13.11.33 (ALOX15 protein, human)
EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
GAN16C9B8O (Glutathione)
تواريخ الأحداث: Date Created: 20211111 Date Completed: 20220218 Latest Revision: 20220218
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8718153
DOI: 10.1172/JCI151685
PMID: 34762602
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI151685