Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria.
Sepsis, a life-threatening complication of infections and the most common cause of death in intensive care units, is characterized by a hyperactive and out-of-balance network of endogenous proinflammatory cytokines. None of the current therapies are entirely effective, illustrating the need for novel therapeutic approaches. Ghrelin (GHR) is an orexigenic peptide that has emerged as a potential endogenous anti-inflammatory factor. In this study, we show that the delayed administration of GHR protects against the mortality in various models of established endotoxemia and sepsis. The therapeutic effect of GHR is mainly mediated by decreasing the secretion of the high mobility box 1 (HMGB1), a DNA-binding factor that acts as a late inflammatory factor critical for sepsis progression. Macrophages seem to be the major cell targets in the inhibition of HMGB1 secretion, in which GHR blocked its cytoplasmic translocation. Interestingly, we also report that GHR shows a potent antibacterial activity in septic mice and in vitro. Remarkably, GHR also reduces the severity of experimental arthritis and the release of HMGB1 to serum. Therefore, by regulating crucial processes of sepsis, such as the production of early and late inflammatory mediators by macrophages and the microbial load, GHR represents a feasible therapeutic agent for this disease and other inflammatory disorders.
Institute of Parasitology and Biomedicine, Consejo Superior de Investigaciones Cientificas, Granada, Spain.
Alejo
A
Chorny
Per
P
Anderson
Elena
E
Gonzalez-Rey
Mario
M
Delgado
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D001770:Blood Bactericidal Activity / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D054439:Ghrelin / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000502:physiology / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D021381:Protein Transport / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control*; D013997:Time Factors
D023181:Antimicrobial Cationic Peptides; D054439:Ghrelin; D024243:HMGB1 Protein; D011994:Recombinant Proteins