Khader Adam, Yang Weng-Lang, Hansen Laura W, Rajayer Salil R, Prince Jose M, Nicastro Jeffrey M, Coppa Gene F, Wang Ping
Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Department of Surgery, Hofstra Northwell School of Medicine, Hempstead, New York.
Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Department of Surgery, Hofstra Northwell School of Medicine, Hempstead, New York; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York.
J Surg Res. 2017 Nov;219:288-295. doi: 10.1016/j.jss.2017.06.031. Epub 2017 Jul 10.
Sepsis affects 800,000 patients in the United States annually with a mortality rate of up to 30%. Recent studies suggest that sepsis-associated metabolic derangements due to hypoxic tissue injury, impaired oxygen utilization, and mitochondrial dysfunction contribute to mortality. Sirtuin 1 (Sirt1) is a crucial modulator of energy metabolism during starvation states and has anti-inflammatory effects. Here, we hypothesized that SRT1720, a Sirt1 activator, could attenuate the severity of sepsis.
Male C57BL/6 mice (20-25 g) were subjected to cecal ligation and puncture (CLP) to induce sepsis. SRT1720 (5 or 20 mg/kg BW) or 10% dimethyl sulfoxide (vehicle) in 0.2-mL saline was injected intravenously at 5 h after CLP. Control animals were not subjected to any surgery. Blood and liver samples were harvested at 20 h after CLP for analysis.
Administration of SRT1720 markedly reduced the serum levels of tissue injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) and renal injury markers (blood urea nitrogen and creatinine) in a dose-dependent manner after CLP. Furthermore, the levels of proinflammatory cytokines interleukin (IL)-1β and IL-6 in the serum and liver were significantly inhibited by SRT1720 treatment after CLP. SRT1720 treatment resulted in a significantly decreased mRNA expression of inflammasome components (nucleotide oligomerization domain-like receptor protein 3, adapter apoptosis-associated speck-like protein containing caspase-recruitment domain, IL-1β, and IL-18) in the liver, compared with the vehicle group.
SRT1720 treatment attenuates multiorgan injury in septic mice. SRT1720 treatment also decreases the production of proinflammatory cytokines and reduces inflammasome activation. Thus, pharmacologic stimulation of Sirt1 may present a promising therapeutic strategy for sepsis.
在美国，脓毒症每年影响80万名患者，死亡率高达30%。最近的研究表明，由于缺氧性组织损伤、氧利用受损和线粒体功能障碍导致的脓毒症相关代谢紊乱会导致死亡。沉默调节蛋白1（Sirt1）是饥饿状态下能量代谢的关键调节因子，具有抗炎作用。在此，我们假设Sirt1激活剂SRT1720可以减轻脓毒症的严重程度。
将雄性C57BL/6小鼠（20 - 25克）进行盲肠结扎和穿刺（CLP）以诱导脓毒症。在CLP后5小时，将SRT1720（5或20毫克/千克体重）或0.2毫升盐水中的10%二甲基亚砜（载体）静脉注射。对照动物不进行任何手术。在CLP后20小时采集血液和肝脏样本进行分析。
CLP后，给予SRT1720以剂量依赖的方式显著降低了组织损伤标志物（天冬氨酸转氨酶、丙氨酸转氨酶和乳酸脱氢酶）和肾损伤标志物（血尿素氮和肌酐）的血清水平。此外，CLP后SRT1720治疗显著抑制了血清和肝脏中促炎细胞因子白细胞介素（IL）-1β和IL-6的水平。与载体组相比，SRT1720治疗导致肝脏中炎性小体成分（核苷酸寡聚化结构域样受体蛋白3、含半胱天冬酶招募结构域的衔接蛋白凋亡相关斑点样蛋白、IL-1β和IL-18）的mRNA表达显著降低。
SRT1720治疗可减轻脓毒症小鼠的多器官损伤。SRT1720治疗还可减少促炎细胞因子的产生并降低炎性小体的激活。因此，对Sirt1进行药物刺激可能是一种有前途的脓毒症治疗策略。
