Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
J Immunol. 2010 Jul 1;185(1):517-24. doi: 10.4049/jimmunol.0903975. Epub 2010 Jun 2.
The adipose-derived hormone leptin is well known for its contribution to energy metabolism and satiety signaling in the hypothalamus. Previous studies suggested that obesity is an independent risk factor for sepsis morbidity and mortality, and it is associated with elevated baseline levels of circulating leptin in normal, nonseptic patients. In mouse endotoxemia and cecal ligation puncture models of sepsis, we observed elevated levels of leptin and soluble leptin receptor (sLR). Exogenously administered leptin increased mortality in endotoxemia and cecal ligation puncture models and was associated with increased expression of adhesion and coagulation molecules, macrophage infiltration into the liver and kidney, and endothelial barrier dysfunction. Conversely, longform leptin receptor-deficient mice were protected from sepsis morbidity and mortality and had less endothelial dysfunction. Furthermore, an in vitro study revealed that leptin-induced endothelial dysfunction is likely mediated, at least in part, by monocytes. Moreover, administration of an sLR conferred a survival benefit. Human septic patients have increased circulating sLR concentrations, which were correlated with disease severity indices. Together, these data support a pathogenic role for leptin signaling during sepsis.
脂肪组织分泌的激素瘦素（leptin）在调节能量代谢和下丘脑饱腹感信号方面发挥着重要作用。既往研究表明肥胖是脓毒症发病率和死亡率的独立危险因素，且与非脓毒症患者循环瘦素水平升高有关。在脓毒症的小鼠内毒素血症和盲肠结扎穿刺模型中，我们观察到瘦素和可溶性瘦素受体（sLR）水平升高。外源性给予瘦素可增加内毒素血症和盲肠结扎穿刺模型的死亡率，并与黏附分子和凝血分子的表达增加、巨噬细胞浸润到肝脏和肾脏以及内皮屏障功能障碍相关。相反，长型瘦素受体缺陷型小鼠对脓毒症的发病率和死亡率具有保护作用，且内皮功能障碍较少。此外，一项体外研究表明，瘦素诱导的内皮功能障碍可能至少部分由单核细胞介导。另外，sLR 的给药可带来生存获益。脓毒症患者的循环 sLR 浓度升高，与疾病严重程度指数相关。综上所述，这些数据支持瘦素信号在脓毒症中的致病作用。
