Insulin-like growth factor-1 improves survival in sepsis via enhanced hepatic bacterial clearance

Alix Ashare; Amanda B Nymon; Kevin C Doerschug; John M Morrison; Martha M Monick; Gary W Hunninghake

doi:10.1164/rccm.200709-1400OC

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Insulin-like growth factor-1 improves survival in sepsis via enhanced hepatic bacterial clearance

Journal article

Open access

Peer reviewed

Insulin-like growth factor-1 improves survival in sepsis via enhanced hepatic bacterial clearance

Alix Ashare, Amanda B Nymon, Kevin C Doerschug, John M Morrison, Martha M Monick and Gary W Hunninghake

American journal of respiratory and critical care medicine, Vol.178(2), pp.149-157

07/15/2008

DOI: 10.1164/rccm.200709-1400OC

PMCID: PMC2453509

PMID: 18436791

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Abstract

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

Insulin-Like Growth Factor I - pharmacology

Microbial Viability - drug effects

Apoptosis - drug effects

Pseudomonas Infections - drug therapy

Humans

Mice, Inbred C57BL

Cells, Cultured

Inflammation

Recombinant Proteins

Case-Control Studies

Kupffer Cells - drug effects

Sepsis - drug therapy

Pseudomonas Infections - metabolism

Animals

Analysis of Variance

Survival Analysis

Insulin-Like Growth Factor I - adverse effects

Kupffer Cells - metabolism

Mice

Sepsis - blood

Insulin-Like Growth Factor I - metabolism

Details

Title: Subtitle: Insulin-like growth factor-1 improves survival in sepsis via enhanced hepatic bacterial clearance
Creators: Alix Ashare - 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
Amanda B Nymon
Kevin C Doerschug
John M Morrison
Martha M Monick
Gary W Hunninghake
Resource Type: Journal article
Publication Details: American journal of respiratory and critical care medicine, Vol.178(2), pp.149-157
DOI: 10.1164/rccm.200709-1400OC
PMID: 18436791
PMCID: PMC2453509
NLM abbreviation: Am J Respir Crit Care Med
ISSN: 1073-449X
eISSN: 1535-4970
Grant note: HL-073967-02 / NHLBI NIH HHS K08 DK073519 / NIDDK NIH HHS HL-077431-01 / NHLBI NIH HHS K08DK073519 / NIDDK NIH HHS R01 HL079901 / NHLBI NIH HHS UL1 RR024979 / NCRR NIH HHS R01 HL079901-05 / NHLBI NIH HHS
Language: English
Date published: 07/15/2008
Academic Unit: Pulmonary, Critical Care, and Occupational Medicine; Internal Medicine
Record Identifier: 9984094634602771

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