Teoh Hwee, Quan Adrian, Bang K W Annie, Wang Guilin, Lovren Fina, Vu Vivian, Haitsma Jack J, Szmitko Paul E, Al-Omran Mohammed, Wang Chao-Hung, Gupta Milan, Peterson Mark D, Zhang Haibo, Chan Lawrence, Freedman John, Sweeney Gary, Verma Subodh
Div. of Cardiovascular and Thoracic Surgery, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E658-64. doi: 10.1152/ajpendo.90384.2008. Epub 2008 Jul 15.
Sepsis is a multifactorial, and often fatal, disorder typically characterized by widespread inflammation and immune activation with resultant endothelial activation. In the present study, we postulated that the adipokine adiponectin serves as a critical modulator of survival and endothelial activation in sepsis. To this aim, we evaluated both loss-of-function (adiponectin gene-deficient mice) and subsequent gain-of-function (recombinant adiponectin reconstitution) strategies in two well-established inflammatory models, cecal ligation perforation (CLP) and thioglyocollate-induced peritonitis. Adipoq(-/-) mice, subjected to CLP, exhibited a profound ( approximately 8-fold) reduction in survival compared with their wild-type Adipoq(+/+) littermates after 48 h. Furthermore, compared with wild-type controls, thioglycollate challenge resulted in a markedly greater influx of peritoneal neutrophils in Adipoq(-/-) mice accompanied by an excess production of key chemoattractant cytokines (IL-12p70, TNFalpha, MCP-1, and IL-6) and upregulation of aortic endothelial adhesion molecule VCAM-1 and ICAM-1 expressions. Importantly, all of these effects were blunted by recombinant total adiponectin administration given 3 days prior to thioglycollate challenge. The protective effects of adiponectin were ascribed largely to higher-order adiponectin oligomers, since administration of recombinant C39A trimeric adiponectin did not attenuate endothelial adhesion molecule expression in thioglycollate-challenged Adipoq(-/-) mice. These data suggest a critical role of adiponectin as a modulator of survival and endothelial inflammation in experimental sepsis and a potential mechanistic link between adiposity and increased sepsis.
脓毒症是一种多因素且通常致命的病症，其典型特征为广泛的炎症反应和免疫激活，进而导致内皮细胞激活。在本研究中，我们推测脂肪因子脂联素是脓毒症中生存和内皮细胞激活的关键调节因子。为此，我们在两种成熟的炎症模型，即盲肠结扎穿孔（CLP）和巯基乙酸盐诱导的腹膜炎中，评估了功能丧失（脂联素基因缺陷小鼠）和随后的功能获得（重组脂联素重建）策略。接受CLP的Adipoq(-/-)小鼠在48小时后与野生型Adipoq(+/+)同窝小鼠相比，生存率显著降低（约8倍）。此外，与野生型对照组相比，巯基乙酸盐刺激导致Adipoq(-/-)小鼠腹腔中性粒细胞大量涌入，同时关键趋化因子细胞因子（IL-12p70、TNFα、MCP-1和IL-6）过度产生，主动脉内皮黏附分子VCAM-1和ICAM-1表达上调。重要的是，在巯基乙酸盐刺激前3天给予重组总脂联素可减弱所有这些效应。脂联素的保护作用主要归因于高阶脂联素寡聚体，因为给予重组C39A三聚体脂联素并不能减弱巯基乙酸盐刺激的Adipoq(-/-)小鼠中内皮黏附分子的表达。这些数据表明脂联素在实验性脓毒症中作为生存和内皮炎症调节因子的关键作用，以及肥胖与脓毒症增加之间潜在的机制联系。
