國家衛生研究院 NHRI:Item 3990099045/8775
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    題名: Statin-conferred enhanced cellular resistance against bacterial pore-forming toxins in airway epithelial cells
    作者: Statt, S;Ruan, JW;Hung, LY;Chang, CY;Huang, CT;Lim, JH;Li, JD;Wu, R;Kao, CY
    貢獻者: Immunology Research Center
    摘要: Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in septic and pneumonia patients, although molecular mechanisms have mostly remained unclear. Using human airway epithelial cells as a proper in vitro model, we show that prior exposure to physiological nanomolar serum concentrations of simvastatin (ranging from 10nM to 1000nM) confers significant cellular resistance to the cytotoxicity of pneumolysin, a pore-forming toxin and the main virulence factor of Streptococcus pneumoniae. This protection could be demonstrated with a different statin, pravastatin, or on a different toxin, alpha-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immuno-fluorescence microscopy, and biochemical and metabolic rescue approaches, we demonstrate that the mechanism of protection conferred by simvastatin at physiological nanomolar concentrations could be different from the canonical mevalonate pathways seen in most other mechanistic studies conducted with statins at micromolar levels. All of these data are integrated into a protein synthesis-dependent, calcium-dependent model showing the interconnected pathways used by statins in airway epithelial cells to elicit an increased resistance to pore-forming toxins. This research fills large gaps in our understanding of how statins may confer host cellular protection against bacterial infections in the context of airway epithelial cells without the confounding effect from the presence of immune cells. In addition, our discovery could be potentially developed into a host-centric strategy for the adjuvant treatment of pore-forming toxin-associated bacterial infections.
    日期: 2015-11
    關聯: American Journal of Respiratory Cell and Molecular Biology. 2015 Nov;53(5):689-702.
    Link to: http://dx.doi.org/10.1165/rcmb.2014-0391OC
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1044-1549&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000368418700011
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84930624257
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