Intravenous delivery of granulocyte-macrophage colony stimulating factor impairs survival in lipopolysaccharide-induced sepsis.

Jörg Krebs,Burkhard Tönshoff,Neysan Rafat,Benito Yard,Grietje Beck,Christian Patry,Charalambos Tsagogiorgas,Alexander Hillenbrand,Partha Mukhopadhyay

doi:10.1371/journal.pone.0218602

Abstract

BackgroundCell-based therapies with bone marrow-derived progenitor cells (BMDPC) lead to an improved clinical outcome in animal sepsis models. In the present study we evaluated the ability of granulocyte macrophage-colony stimulating factor (GM-CSF) to mobilize BMDPC in a lipopolysaccharide (LPS)-induced sepsis model and thereby its potential as a novel treatment strategy.MethodsMale Wistar rats received LPS (25μg/kg/h for 4 days) intravenously and were subsequently treated with GM-CSF 12.5μg/kg (0h,24h,48h,72h). As control groups, rats were infused with sodium chloride or GM-CSF only. Clinical and laboratory parameters, proinflammatory plasma cytokines as well as BMDPC counts were analyzed. Cytokine release by isolated peripheral blood mononuclear cells from rat spleen upon incubation with LPS, GM-CSF and a combination of both were investigated in vitro.ResultsIn vivo, rats receiving both LPS and GM-CSF, showed a reduced weight loss and increased mobilization of BMDPC. At the same time, this regime resulted in an increased release of proinflammatory cytokines (IL-6, IL-8) and a significantly increased mortality. In vitro, the combination of LPS and GM-CSF showed a significantly increased IL-6 release upon incubation compared to incubation with LPS or GM-CSF alone.ConclusionsGM-CSF did not have a beneficial effect on the clinical course in our LPS-induced sepsis model. It synergistically promoted inflammation with LPS and probably thereby impaired survival.

Highlights

Septic shock with multiple organ failure is the leading cause of death in intensive care units and remains a major health problem
The combination of LPS and granulocyte macrophage colony-stimulating factor (GM-CSF) showed a significantly increased IL-6 release upon incubation compared to incubation with LPS or GM-CSF alone
The mobilization and recruitment of endothelial progenitor cells (EPC)/bone marrow-derived progenitor cells (BMDPC) is mediated by soluble factors such as vascular endothelial growth factor (VEGF), granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO) and angiopoetin- (ANG)-2 [16] and offers a particular therapeutic potential

Summary

Introduction

Septic shock with multiple organ failure is the leading cause of death in intensive care units and remains a major health problem. A potential treatment strategy could be the use of endothelial progenitor cells (EPC) [6,7], which have been shown to play a role [8,9,10,11,12]. The mobilization and recruitment of EPC/BMDPC is mediated by soluble factors such as vascular endothelial growth factor (VEGF), granulocyte macrophage colony-stimulating factor (GM-CSF), erythropoietin (EPO) and angiopoetin- (ANG)-2 [16] and offers a particular therapeutic potential. Cell-based therapies with bone marrow-derived progenitor cells (BMDPC) lead to an improved clinical outcome in animal sepsis models. In the present study we evaluated the ability of granulocyte macrophage-colony stimulating factor (GM-CSF) to mobilize BMDPC in a lipopolysaccharide (LPS)-induced sepsis model and thereby its potential as a novel treatment strategy

Methods

Results

Conclusion