Ghrelin attenuates sepsis-induced acute lung injury and mortality in rats.
BACKGROUND
Our study has shown that plasma levels of ghrelin, a stomach-derived peptide, are significantly reduced in sepsis, and that ghrelin administration improves organ blood flow via a nuclear factor (NF)-kappaB-dependent pathway. However, it remains unknown whether ghrelin has any protective effects on severe sepsis-induced acute lung injury (ALI) and, if so, whether inhibition of NF-kappaB plays any role in it.


OBJECTIVE
To test the hypothesis that ghrelin reduces severe sepsis-induced ALI and mortality through inhibition of NF-kappaB.


METHODS
Sepsis was induced in rats by cecal ligation and puncture (CLP). Five hours after CLP, a bolus intravenous injection of 2 nmol of ghrelin was followed by continuous infusion of 12 nmol of ghrelin via a minipump for 15 hours. Samples were harvested 20 hours post-CLP (i.e., severe sepsis). Pulmonary levels of ghrelin and proinflammatory cytokines were measured by ELISA. NF-kappaB p65 and IkappaBalpha expression and NF-kappaB activity were measured by Western blot analysis and ELISA, respectively. Pulmonary blood flow was measured with radioactive microspheres. In additional animals, the necrotic cecum was excised 20 hours post-CLP and 10-day survival was recorded.


RESULTS
Pulmonary levels of ghrelin decreased significantly 20 hours post-CLP. Ghrelin administration restored pulmonary levels of ghrelin, reduced lung injury, increased pulmonary blood flow, down-regulated proinflammatory cytokines, inhibited NF-kappaB activation, and improved survival in sepsis. Administration of a specific ghrelin receptor antagonist worsened the survival rate after CLP and cecal excision.


CONCLUSIONS
Ghrelin can be developed as a novel treatment for severe sepsis-induced ALI. The protective effect of ghrelin is mediated through inhibition of NF-kappaB.
Wu
Rongqian
R
Department of Surgery, North Shore University Hospital, Manhasset, New York, USA.
Dong
Weifeng
W
Zhou
Mian
M
Zhang
Fangming
F
Marini
Corrado P
CP
Ravikumar
Thanjavur S
TS
Wang
Ping
P
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D054439:Ghrelin / Q000378:metabolism / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D055370:Lung Injury; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018377:Neurotransmitter Agents / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D018805:Sepsis / Q000150:complications*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016207:Cytokines; D054439:Ghrelin; D015850:Interleukin-6; D016328:NF-kappa B; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D013373:Substance P; C045800:substance P, Phe(5)-Trp(7,9)-Leu(11)-