Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve.
OBJECTIVE
To test the hypothesis that administration of ghrelin attenuates inflammatory responses in sepsis through vagal nerve stimulation.


BACKGROUND
Ghrelin has been demonstrated to possess multiple functions, including stimulation of the vagus nerve. Our recent study has shown that plasma levels of ghrelin were significantly reduced in sepsis; and ghrelin administration improved organ perfusion and function. However, it remained unknown whether ghrelin also decreases proinflammatory cytokines in sepsis and, if so, whether the down-regulatory effect of ghrelin is mediated by activation of the vagus nerve.


METHODS
Male rats were subjected to sepsis by cecal ligation and puncture (CLP). At 5 hours after CLP, a bolus intravenous injection of 2 nmol ghrelin was followed by a continuous infusion of 12 nmol ghrelin via a primed 200-microL Alzet mini-pump for 15 hours. At 20 hours after CLP, plasma and peritoneal fluid levels of TNF-alpha and IL-6 were determined. The direct effect of ghrelin on cytokine production was studied using cultured normal rat Kupffer cells or peritoneal macrophages stimulated by lipopolysaccharide (LPS). In additional animals, vagotomy or sham vagotomy was performed in sham and septic animals immediately prior to ghrelin administration and cytokine levels were then measured.


RESULTS
Ghrelin significantly reduced TNF-alpha and IL-6 levels in sepsis. In contrast, ghrelin did not inhibit TNF-alpha and IL-6 release from LPS-stimulated Kupffer cells or peritoneal macrophages. However, vagotomy, but not sham vagotomy, prevented ghrelin's down-regulatory effect on TNF-alpha and IL-6 production.


CONCLUSIONS
Ghrelin down-regulates proinflammatory cytokines in sepsis through activation of the vagus nerve. Pharmacologic stimulation of the vagus nerve may offer a novel approach of anti-sepsis therapy.
Wu
Rongqian
R
Department of Surgery, North Shore University Hospital, Manhasset, NY 11030, USA.
Dong
Weifeng
W
Cui
Xiaoxuan
X
Zhou
Mian
M
Simms
H Hank
HH
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D000818:Animals; D015536:Down-Regulation / Q000502:physiology; D054439:Ghrelin; D015850:Interleukin-6 / Q000097:blood; D007728:Kupffer Cells / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D036361:Peptide Hormones / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014630:Vagus Nerve / Q000187:drug effects*
D054439:Ghrelin; D015850:Interleukin-6; D036361:Peptide Hormones; D014409:Tumor Necrosis Factor-alpha