Statt Sarah, Ruan Jhen-Wei, Hung Li-Yin, Chang Ching-Yun, Huang Chih-Ting, Lim Jae Hyang, Li Jian-Dong, Wu Reen, Kao Cheng-Yuan
1 Center for Comparative Respiratory Biology and Medicine, University of California at Davis, Davis, California.
2 Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, Taiwan.
Am J Respir Cell Mol Biol. 2015 Nov;53(5):689-702. doi: 10.1165/rcmb.2014-0391OC.
Statins are widely used to prevent cardiovascular disease. In addition to their inhibitory effects on cholesterol synthesis, statins have beneficial effects in patients with sepsis and pneumonia, 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 10-1,000 nM) 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, α-hemolysin. Furthermore, through the use of gene silencing, pharmacological inhibitors, immunofluorescence 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.
他汀类药物被广泛用于预防心血管疾病。除了对胆固醇合成的抑制作用外，他汀类药物对脓毒症和肺炎患者也有有益作用，尽管其分子机制大多仍不清楚。我们使用人气道上皮细胞作为合适的体外模型，发现预先暴露于生理纳摩尔血清浓度的辛伐他汀（范围为10 - 1000 nM）可使细胞对肺炎溶素的细胞毒性产生显著抗性，肺炎溶素是一种形成孔道的毒素，也是肺炎链球菌的主要毒力因子。使用不同的他汀类药物普伐他汀或针对不同的毒素α-溶血素也能证明这种保护作用。此外，通过基因沉默、药理学抑制剂、免疫荧光显微镜以及生化和代谢挽救方法，我们证明生理纳摩尔浓度的辛伐他汀所赋予的保护机制可能不同于大多数其他用微摩尔水平他汀类药物进行的机制研究中所看到的经典甲羟戊酸途径。所有这些数据整合到一个蛋白质合成依赖性、钙依赖性模型中，该模型展示了他汀类药物在气道上皮细胞中用于引发对形成孔道毒素抗性增加的相互关联途径。这项研究填补了我们在理解他汀类药物如何在气道上皮细胞背景下赋予宿主细胞对细菌感染的保护作用方面的巨大空白，而不存在免疫细胞存在带来的混杂影响。此外，我们的发现有可能发展成为一种以宿主为中心的策略，用于辅助治疗与形成孔道毒素相关的细菌感染。
