title: Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in interstitial lung disease.
abstract: Aberrant antioxidant activity and excessive deposition of extracellular matrix (ECM) are hallmarks of interstitial lung diseases (ILD). It is known that oxidative stress alters the ECM, but extracellular antioxidant defence mechanisms in ILD are incompletely understood. Here, we extracted abundance and detergent solubility of extracellular antioxidant enzymes from a proteomic dataset of bleomycin-induced lung fibrosis in mice and assessed regulation and distribution of glutathione peroxidase 3 (GPX3) in murine and human lung fibrosis. Superoxide dismutase 3 (Sod3), Gpx3, and Gpx activity were increased in mouse BALF during bleomycin-induced lung fibrosis. In lung tissue homogenates, Gpx3, but not Sod3, was upregulated and detergent solubility profiling indicated that Gpx3 associated with ECM proteins. Immunofluorescence analysis showed that Gpx3 was expressed by bronchial epithelial cells and interstitial fibroblasts and localized to the basement membrane and interstitial ECM in lung tissue. As to human ILD samples, BALF of some patients contained high levels of GPX3, and GPX3 was upregulated in lung homogenates from IPF patients. GPX3 expression in primary human bronchial epithelial cells and lung fibroblasts was downregulated by TNF-α, but more variably regulated by TGF-β1 and menadione. In conclusion, the antioxidant enzyme GPX3 localizes to lung ECM and is variably upregulated in ILD.
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Schamberger
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.|Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Herbert B
authors.initials: HB
authors.lastname: Schiller
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Isis E
authors.initials: IE
authors.lastname: Fernandez
authors.affiliation: Department of Respiratory Medicine of the 1st Medical School, Charles University and Thomayer Hospital, Prague, Czech republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Sterclova
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heinzelmann
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Hennen
authors.affiliation: Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, Ludwig-Maximilians-Universität, Munich, Germany.|Asklepios Fachkliniken München-Gauting, Munich, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Hatz
authors.affiliation: Asklepios Fachkliniken München-Gauting, Munich, Germany.|Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Member of the German Center for Lung Research (DZL), Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Behr
authors.affiliation: Department of Respiratory Medicine of the 1st Medical School, Charles University and Thomayer Hospital, Prague, Czech republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Vašáková
authors.affiliation: Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Comprehensive Pneumology Center, Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL), Munich, Germany.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Staab-Weijnitz
mesh_terms: D000368:Aged; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001761:Bleomycin; D001980:Bronchi / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D003710:Demography; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000201:enzymology*; D005109:Extracellular Matrix / Q000201:enzymology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000201:enzymology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D024483:Vitamin K 3; C486484:GPX3 protein, human; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase