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
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute-Phase Proteins / antagonists & inhibitors
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Acute-Phase Proteins / genetics
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Acute-Phase Proteins / metabolism*
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Animals
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Granulocyte Colony-Stimulating Factor / metabolism*
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Lipopolysaccharide Receptors / metabolism
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Lipopolysaccharides / toxicity*
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Liver / drug effects
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Liver / metabolism*
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Liver / pathology
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Male
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Membrane Glycoproteins / antagonists & inhibitors
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Peptides / pharmacology
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Rats
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Systemic Inflammatory Response Syndrome / chemically induced
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Systemic Inflammatory Response Syndrome / metabolism*
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Systemic Inflammatory Response Syndrome / pathology
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Toll-Like Receptor 4 / genetics
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Toll-Like Receptor 4 / metabolism
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Up-Regulation
Substances
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Acute-Phase Proteins
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Carrier Proteins
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LPS binding protein (86-99), Ala(95)-
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Lipopolysaccharide Receptors
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Lipopolysaccharides
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Membrane Glycoproteins
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Peptides
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Toll-Like Receptor 4
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lipopolysaccharide-binding protein
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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.