title: Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.
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.affiliation: Div. of Cardiovascular and Thoracic Surgery, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
authors.forename: Hwee
authors.initials: H
authors.lastname: Teoh
authors.forename: Adrian
authors.initials: A
authors.lastname: Quan
authors.forename: K W Annie
authors.initials: KW
authors.lastname: Bang
authors.forename: Guilin
authors.initials: G
authors.lastname: Wang
authors.forename: Fina
authors.initials: F
authors.lastname: Lovren
authors.forename: Vivian
authors.initials: V
authors.lastname: Vu
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Haitsma
authors.forename: Paul E
authors.initials: PE
authors.lastname: Szmitko
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Omran
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Milan
authors.initials: M
authors.lastname: Gupta
authors.forename: Mark D
authors.initials: MD
authors.lastname: Peterson
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: John
authors.initials: J
authors.lastname: Freedman
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D052242:Adiponectin / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D000818:Animals; D002432:Cecum / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D004727:Endothelium / Q000502:physiology*; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007416:Intestinal Perforation / Q000473:pathology; D007958:Leukocyte Count; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D010538:Peritonitis / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D018805:Sepsis / Q000235:genetics / Q000401:mortality* / Q000503:physiopathology*; D016019:Survival Analysis; D013864:Thioglycolates
chemical_list: D052242:Adiponectin; D016207:Cytokines; D011994:Recombinant Proteins; D013864:Thioglycolates