The Synthetic Tie2 Agonist Peptide Vasculotide Protects Against Vascular Leakage and Reduces Mortality in Murine Abdominal Sepsis

DSpace/Manakin Repository

The Synthetic Tie2 Agonist Peptide Vasculotide Protects Against Vascular Leakage and Reduces Mortality in Murine Abdominal Sepsis

Citable link to this page

 

 
Title: The Synthetic Tie2 Agonist Peptide Vasculotide Protects Against Vascular Leakage and Reduces Mortality in Murine Abdominal Sepsis
Author: Kümpers, Philipp; Gueler, Faikah; David, Sascha; Van Slyke, Paul; Dumont, Daniel J; Park, Joon-Keun; Bockmeyer, Clemens L; Pavenstädt, Hermann; Haller, Hermann; Shushakova, Nelli; Parikh, Samir Mukund

Note: Order does not necessarily reflect citation order of authors.

Citation: Kümpers, Philipp, Faikah Gueler, Sascha David, Paul Van Slyke, Daniel J. Dumont, Joon-Keun Park, Clemens L. Bockmeyer, et al. 2011. The synthetic Tie2 agonist peptide vasculotide protects against vascular leakage and reduces mortality in murine abdominal sepsis. Critical Care 15(5): R261.
Full Text & Related Files:
Abstract: Introduction: Angiopoietin-1 (Angpt1), the natural agonist ligand for the endothelial Tie2 receptor, is a non-redundant endothelial survival and vascular stabilization factor that reduces endothelial permeability and inhibits leukocyte-endothelium interactions. Here we evaluate the efficacy of a novel polyethylene glycol (PEG)-clustered Tie2 agonist peptide, vasculotide (VT), to protect against vascular leakage and mortality in a murine model of polymicrobial abdominal sepsis. Methods: Polymicrobial abdominal sepsis in C57BL6 mice was induced by cecal-ligation-and-puncture (CLP). Mice were treated with different dosages of VT or equal volume of phosphate-buffered saline (PBS). Sham-operated animals served as time-matched controls. Results: Systemic administration of VT induced long-lasting Tie2 activation in vivo. VT protected against sepsis-induced endothelial barrier dysfunction, as evidenced by attenuation of vascular leakage and leukocyte transmigration into the peritoneal cavity. Histological analysis revealed that VT treatment ameliorated leukocyte infiltration in kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression. VT-driven effects were associated with significantly improved organ function and reduced circulating cytokine levels. The endothelial-specific action of VT was supported by additional in vitro studies showing no effect of VT on either cytokine release from isolated peritoneal macrophages, or migratory capacity of isolated neutrophils. Finally, administration of VT pre-CLP (hazard ratio 0.39 [95% confidence interval 0.19-0.81] P < 0.001) and post-CLP reduced mortality in septic mice (HR 0.22 [95% CI 0.06-0.83] P < 0.05). Conclusions: We provide proof of principle in support of the efficacious use of PEGylated VT, a drug-like Tie2 receptor agonist, to counteract microvascular endothelial barrier dysfunction and reduce mortality in a clinically relevant murine sepsis model. Further studies are needed to pave the road for clinical application of this therapeutic concept.
Published Version: doi:10.1186/cc10523
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334812/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10352026
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters