Orexigenic hormone ghrelin ameliorates gut barrier dysfunction in sepsis in rats.
OBJECTIVE
We have recently shown that ghrelin, a novel orexigenic hormone, is reduced in sepsis. Ghrelin treatment, mediated through ghrelin receptors in the brain, attenuates sepsis-induced inflammation and mortality. Gut barrier dysfunction is common in sepsis. High-mobility group B1 (HMGB1) increases gut permeability both in vitro and in vivo. However, it remains unknown whether ghrelin has any effects on HMGB1 and gut barrier function in sepsis. We hypothesized that ghrelin decreases HMGB1 release and attenuates sepsis-induced gut barrier dysfunction through central ghrelin receptors.


METHODS
Prospective, controlled, and randomized animal study.


METHODS
A research institute laboratory.


METHODS
Male adult Sprague-Dawley rats (275-325 g).


METHODS
Cecal ligation and puncture (CLP) followed by injection/infusion of ghrelin.


RESULTS
Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by a continuous infusion of 12 nmol of ghrelin via an osmotic mini-pump for 15 hrs. Twenty hours after CLP, brain ghrelin levels, serum HMGB1 levels, ileal mucosal permeability to fluorescein isothiocyanate dextran, bacterial counts in the mesenteric lymph nodes complex, and gut water content were determined. In additional groups of animals, bilateral trunk vagotomy was performed at 5 hrs after CLP before ghrelin injection. Furthermore, to confirm the role of central ghrelin receptors in ghrelin's effect, ghrelin (1 nmol) was administered through intracerebroventricular injection at 5 hrs after CLP. Our results showed that brain levels of ghrelin decreased by 34% at 20 hrs after CLP. Intravenous administration of ghrelin completely restored brain levels of ghrelin, significantly reduced the elevated HMGB1 levels, and attenuated gut barrier dysfunction. Vagotomy eliminated ghrelin's inhibition of HMGB1 and attenuation of gut barrier dysfunction. Intracerebroventricular injection of ghrelin decreased serum HMGB1 levels and ameliorated gut barrier dysfunction.


CONCLUSIONS
Ghrelin reduces serum HMGB1 levels and ameliorates gut barrier dysfunction in sepsis by vagus nerve activation via central ghrelin receptors. Ghrelin can be further developed as a novel agent to protect gut barrier function in sepsis.
Wu
Rongqian
R
Department of Surgery, North Shore University Hospital and Long Island Jewish Medical Center, Manhasset, New York, USA.
Dong
Weifeng
W
Qiang
Xiaoling
X
Wang
Haichao
H
Blau
Steven A
SA
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D000818:Animals; D054439:Ghrelin / Q000494:pharmacology* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors*; D007410:Intestinal Diseases / Q000188:drug therapy* / Q000209:etiology; D007413:Intestinal Mucosa / Q000187:drug effects*; D008297:Male; D010539:Permeability / Q000187:drug effects; D011446:Prospective Studies; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000150:complications / Q000188:drug therapy*
D054439:Ghrelin; D024243:HMGB1 Protein