title: Streptococcus pneumoniae-Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol.
abstract: BACKGROUND
  Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized.
  
  
  METHODS
  For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP.
  
  
  RESULTS
  We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells.
  
  
  CONCLUSIONS
  These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia.
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Janine
authors.initials: J
authors.lastname: Zahlten
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Jan-Moritz
authors.initials: JM
authors.lastname: Doehn
authors.affiliation: Department Genetics of Microorganisms, Institute of Genetics and Functional Genomics, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pribyl
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Andreas C
authors.initials: AC
authors.lastname: Hocke
authors.affiliation: Departamento de Microbiología Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIBER de Enfermedades Respiratorias, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: García
authors.affiliation: Department Genetics of Microorganisms, Institute of Genetics and Functional Genomics, Ernst-Moritz-Arndt-University, Greifswald, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hammerschmidt
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hippenstiel
authors.affiliation: Department of Internal Medicine/Infectious Diseases and Respiratory Medicine, Charité-Universitätsmedizin Berlin.
authors.forename: Ralf-Harto
authors.initials: RH
authors.lastname: Hübner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001329:Autolysis; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D004847:Epithelial Cells / Q000276:immunology; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008168:Lung / Q000276:immunology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000382:microbiology / Q000503:physiopathology; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000276:immunology*; D013301:Streptolysins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001426:Bacterial Proteins; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; D013267:Stilbenes; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D006861:Hydrogen Peroxide; D005978:Glutathione; D000077185:Resveratrol; D019803:Glutathione Disulfide
keywords: Nuclear factor erythroid 2-related factor 2; Streptococcus pneumoniae; autolysin; glutathione; hydrogen peroxide; lung epithelial cells; pneumolysin