title: Lipopolysaccharide-binding protein (LBP) blockade augments the protective effect of granulocyte colony-stimulating factor (G-CSF) in a rat sepsis model.
abstract: The effect of granulocyte colony-stimulating factor (G-CSF) on sepsis is discussed controversially in clinical studies. We previously demonstrated that G-CSF treatment induced lipopolysaccharide (LPS) sensitization via up-regulation of LPS-binding protein (LBP). We hypothesized that the futile effect of G-CSF-treatment in sepsis might be due to its ability to up-regulate LBP. Therefore, blockade of LBP may attenuate the G-CSF-induced LPS sensitization and protect animals from polymicrobial sepsis. Endogenous LBP levels were up-regulated by pretreatment with G-CSF, and the LBP protein was blocked by administration of a specific blocking peptide-LBPK95A. Polymicrobial sepsis was induced by intraperitoneal injection of feces slurry. Rats were monitored every 3 up to 72 h to observe the survival rate. Tissue injury, bacterial infiltration, local inflammatory response, and neutrophil infiltration at 0, 2, and 12 h after the septic insult were analyzed. The survival benefit of G-CSF pretreatment was improved when combined with LBPK95A treatment (control vs. G-CSF vs. combi: 36% vs. 56% vs. 93%; P < 0.05). Combined treatment of G-CSF and LBPK95A was associated with the minimal tissue damage. Treatment with LBPK95A significantly inhibited the neutrophil infiltration without interfering with the bacterial clearance. The G-CSF-induced inflammatory sensitization effect was inhibited by LBPK95A, indicated by the decrease of cytokines expression, and the activation of nuclear factor kappa B and signal transducer and activator of transcription 3 signaling pathway. In conclusion, these results suggested that the effect of prophylactic augmentation of the host's response via G-CSF pretreatment was further enhanced by inhibition of the up-regulation of LBP.
authors: *Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; †Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany; ‡Department of Pathophysiology, Anhui Medical University, Hefei, China; §Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; ∥Institute of Medical Microbiology, Jena University Hospital, Jena, Germany; and ¶Institute for Pathology, Jena University Hospital, Jena, Germany.
authors: Anding
authors: A
authors: Liu
authors: Stefanie
authors: S
authors: Weiss
authors: Haoshu
authors: H
authors: Fang
authors: Ralf A
authors: RA
authors: Claus
authors: Jürgen
authors: J
authors: Rödel
authors: Olaf
authors: O
authors: Dirsch
authors: Uta
authors: U
authors: Dahmen
mesh_terms: D000209:Acute-Phase Proteins / Q000737:chemistry*; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry*; D005243:Feces; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D007249:Inflammation; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry*; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D050796:STAT3 Transcription Factor / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D016179:Granulocyte Colony-Stimulating Factor; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D050796:STAT3 Transcription Factor; D000099231:Lipopolysaccharide-Binding Protein; C555065:LPS binding protein (86-99), Ala(95)-; C494088:Stat3 protein, rat