Streptococcus pneumoniae-Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol

• Published in: The Journal of infectious diseases Vol. 211; no. 11; pp. 1822 - 1830
• Main Authors: Zahlten, Janine, Kim, Ye-Ji, Doehn, Jan-Moritz, Pribyl, Thomas, Hocke, Andreas C., García, Pedro, Hammerschmidt, Sven, Suttorp, Norbert, Hippenstiel, Stefan, Hübner, Ralf-Harto
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.06.2015
• Subjects: Animals; Antioxidants - pharmacology; Autolysis; Bacterial Proteins - metabolism; Cell Line; Cell Survival; Epithelial Cells - immunology; Glutathione - metabolism; Glutathione Disulfide - metabolism; Humans; Hydrogen Peroxide - metabolism; Interleukin-8 - metabolism; Lung - immunology; Mice; NF-E2-Related Factor 2 - immunology; NF-E2-Related Factor 2 - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; PATHOGENESIS AND HOST RESPONSE; Pneumonia, Pneumococcal - immunology; Pneumonia, Pneumococcal - microbiology; Pneumonia, Pneumococcal - physiopathology; Stilbenes - pharmacology; Streptococcus; Streptococcus pneumoniae; Streptococcus pneumoniae - immunology; Streptolysins - metabolism; autolysin; glutathione; hydrogen peroxide; pneumolysin; lung epithelial cells; Nuclear factor erythroid 2-related factor 2; Streptococcus pneumoniae
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiu806

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-dehwed 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.