Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis.

Abstract

INTRODUCTION:

Endothelial activation leading to vascular barrier breakdown plays an essential role in the pathophysiology of multiple-organ dysfunction syndrome (MODS) in sepsis. Increasing evidence suggests that the function of the vessel-protective factor Angiopoietin-1 (Ang-1), a ligand of the endothelial-specific Tie2 receptor, is inhibited by its antagonist Angiopoietin-2 (Ang-2) during sepsis. In order to reverse the effects of the sepsis-induced suppression of Ang-1 and elevation of Ang-2 we aimed to investigate whether an intravenous injection of recombinant human (rh) Ang-1 protects against MODS in murine sepsis.

METHODS:

Polymicrobiological abdominal sepsis was induced by cecal ligation and puncture (CLP). Mice were treated with either 1 μg of intravenous rhAng-1 or control buffer immediately after CLP induction and every 8h thereafter. Sham-operated animals served as time-matched controls.

RESULTS:

Compared to buffer-treated controls, rhAng-1 treated septic mice showed significant improvements in several hematologic and biochemical indicators of MODS. Moreover, rhAng-1 stabilized endothelial barrier function, as evidenced by inhibition of protein leakage from lung capillaries into the alveolar compartment. Histological analysis revealed that rhAng-1 treatment attenuated leukocyte infiltration in lungs and kidneys of septic mice, probably due to reduced endothelial adhesion molecule expression in rhAng-1 treated mice. Finally, the protective effects of rhAng-1 treatment were reflected by an improved survival time in a lethal CLP model.

CONCLUSIONS:

In a clinically relevant murine sepsis model, intravenous rhAng-1 treatment alone is sufficient to significantly improve a variety of sepsis-associated organ dysfunctions and survival time, most likely by preserving endothelial barrier function. Further studies are needed to pave the road for clinical application of this therapy concept.

• Authors: Sascha David, Joon-Keun Park, Matijs van Meurs, Jan G Zijlstra, Christian Koenecke, Claudia Schrimpf, Nelli Shushakova, Faikah Gueler, Hermann Haller, Philipp Kümpers
• Journal: Cytokine (Cytokine) Vol. 55 Issue 2 Pg. 251-9 (Aug 2011) ISSN: 1096-0023 [Electronic] England
• PMID: 21531574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Angiopoietin-1
• Angiopoietin-2
• Recombinant Proteins
• Receptor Protein-Tyrosine Kinases
• Receptor, TIE-2
• Tek protein, mouse

Topics

• Angiopoietin-1 (genetics, metabolism, therapeutic use)
• Angiopoietin-2 (metabolism)
• Animals
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Mice
• Multiple Organ Failure (drug therapy, etiology, pathology)
• Receptor Protein-Tyrosine Kinases (metabolism)
• Receptor, TIE-2
• Recombinant Proteins (genetics, therapeutic use)
• Sepsis (complications, drug therapy, mortality, pathology)
• Survival Rate