Granulocyte colony stimulating factor induces lipopolysaccharide (LPS) sensitization via upregulation of LPS binding protein in rat

Haoshu Fang; Anding Liu; Jian Sun; Alexandra Kitz; Olaf Dirsch; Uta Dahmen

doi:10.1371/journal.pone.0056654

Granulocyte colony stimulating factor induces lipopolysaccharide (LPS) sensitization via upregulation of LPS binding protein in rat

PLoS One. 2013;8(2):e56654. doi: 10.1371/journal.pone.0056654. Epub 2013 Feb 20.

Authors

Haoshu Fang¹, Anding Liu, Jian Sun, Alexandra Kitz, Olaf Dirsch, Uta Dahmen

Affiliation

¹ Experimental Transplantation Surgery, University Hospital of Jena, Jena, Germany.

Abstract

Liver is the main organ for lipopolysaccharide (LPS) clearance. Sensitization to LPS is associated with the upregulation of LPS-binding protein (LBP) in animal models. Therefore, we hypothesized that LBP could induce LPS sensitization through enhancing hepatic uptake of LPS. In this study, we examined the role of LBP in pathogenesis of LPS induced systemic inflammatory response syndrome (SIRS). LBP expression was upregulated after granulocyte colony stimulating (G-CSF) pretreatment. The effect of LBP was further confirmed by blockade of LBP using LBP blocking peptide--LBPK95A. After G-CSF pretreatment, upregulation of LBP was observed in bone marrow cells and liver. The G-CSF induced LBP upregulation caused LPS hypersensitization in rats as indicated by higher mortality and severer liver damage. Of note, LBP blockade increased the survival rate and attenuated the liver injury. The LBP induced LPS hypersensitization was associated with increased hepatic uptake of LPS and augmented hepatic expression of LPS receptors, such as toll-like receptor (TLR)-4. Furthermore, LBP mediated early neutrophil infiltration, which led to increased monocyte recruitment in liver after LPS administration. In conclusion, G-CSF induced LBP expression could serve as a new model for investigation of LPS sensitization. We demonstrated the crucial role of LBP upregulation in pathogenesis of LPS induced SIRS.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acute-Phase Proteins / antagonists & inhibitors
Acute-Phase Proteins / genetics
Acute-Phase Proteins / metabolism*
Animals
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Granulocyte Colony-Stimulating Factor / metabolism*
Lipopolysaccharide Receptors / metabolism
Lipopolysaccharides / toxicity*
Liver / drug effects
Liver / metabolism*
Liver / pathology
Male
Membrane Glycoproteins / antagonists & inhibitors
Membrane Glycoproteins / genetics
Membrane Glycoproteins / metabolism*
Peptides / pharmacology
Rats
Systemic Inflammatory Response Syndrome / chemically induced
Systemic Inflammatory Response Syndrome / metabolism*
Systemic Inflammatory Response Syndrome / pathology
Toll-Like Receptor 4 / genetics
Toll-Like Receptor 4 / metabolism
Up-Regulation

Substances

Acute-Phase Proteins
Carrier Proteins
LPS binding protein (86-99), Ala(95)-
Lipopolysaccharide Receptors
Lipopolysaccharides
Membrane Glycoproteins
Peptides
Toll-Like Receptor 4
lipopolysaccharide-binding protein
Granulocyte Colony-Stimulating Factor

Grants and funding

This study was supported by the German Federal Ministry for Education and Research (BMBF) Virtual Liver Network. URL: http://www.virtual-liver.de/and Center for Sepsis Control and Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.