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

Research output: Contribution to journalArticle

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)-α 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-α-induced apoptosis by activating the PI-3 kinase pathway and stabilizing the inhibitorof apoptosis protein, XIAP. In the animal model, pretreatment with IGF-1 decreased hepatic TNF-α 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.

Original languageEnglish (US)
Pages (from-to)149-157
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Volume178
Issue number2
DOIs
StatePublished - Jul 15 2008
Externally publishedYes

Keywords

  • Apoptosis
  • Bacteria
  • Infection
  • Macrophage

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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