Insulin-like Growth Factor-1 Improves Survival in Sepsis Via Enhanced Hepatic Bacterial Clearance

Overview

Journal Am J Respir Crit Care Med

Specialty Critical Care

Date 2008 Apr 26

PMID 18436791

Citations 22

Authors

Alix Ashare

Amanda B Nymon

Kevin C Doerschug

John M Morrison

Martha M Monick

Gary W Hunninghake

Affiliations

Soon will be listed here.

Abstract

Rationale: 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.

Objectives: 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.

Measurements And Main 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.

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