Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality Academic Article uri icon

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abstract

  • 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.

authors

  • Teoh, Hwee
  • Quan, Adrian
  • Bang, KW 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

publication date

  • September 2008