Adiponectin deficiency promotes endothelial activation and profoundly exacerbates sepsis-related mortality.
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.
Teoh
Hwee
H
Div. of Cardiovascular and Thoracic Surgery, St. Michael's Hospital, Toronto, ON, Canada M5B 1W8.
Quan
Adrian
A
Bang
K W Annie
KW
Wang
Guilin
G
Lovren
Fina
F
Vu
Vivian
V
Haitsma
Jack J
JJ
Szmitko
Paul E
PE
Al-Omran
Mohammed
M
Wang
Chao-Hung
CH
Gupta
Milan
M
Peterson
Mark D
MD
Zhang
Haibo
H
Chan
Lawrence
L
Freedman
John
J
Sweeney
Gary
G
Verma
Subodh
S
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
D052242:Adiponectin; D016207:Cytokines; D011994:Recombinant Proteins; D013864:Thioglycolates