Insulin-like growth factor-1 improves survival in sepsis via enhanced hepatic bacterial clearance.
BACKGROUND
Both insulin-like growth factor (IGF)-1 and bacterial clearance by Kupffer cells are significantly reduced in severe sepsis. Kupffer cell apoptosis is triggered by tumor necrosis factor (TNF)-alpha and activation of the PI-3 kinase pathway prevents TNF-induced Kupffer cell death.


OBJECTIVE
We evaluated if the marked decline in IGF-1 is related to bacterial clearance in sepsis.


METHODS
Sepsis was induced in C57BL/6 mice by intratracheal inoculation with Pseudomonas aeruginosa (strain PA103). Some mice received IGF-1 24 mg/kg either before infection or 12 hours after infection. In vitro studies were performed using the clonal Kupffer cell line KC13-2.


RESULTS
Sepsis resulted in decreased levels of IGF-1. In vitro studies with KC13-2 cells demonstrated that IGF-1 protected Kupffer cells against TNF-alpha-induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitor of apoptosis protein, XIAP. In the animal model, pretreatment with IGF-1 decreased hepatic TNF-alpha and IL-6, improved hepatic bacterial clearance as demonstrated by real-time polymerase chain reaction with primers specific for P. aeruginosa, and improved survival in severe sepsis. Moreover, we rescued mice from severe sepsis by IGF-1 treatment 12 hours after infection.


CONCLUSIONS
These studies show that the decline in IGF-1 levels in sepsis is related to bacterial clearance and that replacement of IGF-1 in a murine model of sepsis improves overall survival.
Ashare
Alix
A
Division of Pulmonary, Critical Care, and Occupational Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, 200 Hawkins Drive, C-33 GH, Iowa City, IA 52242, USA. alix-ashare@uiowa.edu
Nymon
Amanda B
AB
Doerschug
Kevin C
KC
Morrison
John M
JM
Monick
Martha M
MM
Hunninghake
Gary W
GW
D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016022:Case-Control Studies; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation; D007334:Insulin-Like Growth Factor I / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050296:Microbial Viability / Q000187:drug effects; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000378:metabolism; D011994:Recombinant Proteins; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy*; D016019:Survival Analysis
D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I