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David S, Park JK, Meurs Mv, et al. Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis

Department of Nephrology & Hypertension, Hannover Medical School, Carl-NeubergStrasse1, D- 30625, Hannover, Germany.
Cytokine (Impact Factor: 2.66). 04/2011; 55(2):251-9. DOI: 10.1016/j.cyto.2011.04.005
Source: PubMed

ABSTRACT

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.
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.
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.
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.

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Available from: Sascha David, Jul 23, 2014
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    • "Mice were intraperitoneally injected with 100 μg of a purified, functional grade anti-mouse TNF-α antibody (Ab) (clone MP6-XT3; eBioscience), with 500 μg of anti-mouse IL-6 Ab (MP5-20F3; BioXcell), or with 100 μg of an isotype control Ab (clone P3.6.2.8.1; eBioscience) on Days 1, 2, and 4 p.i. Mice were monitored daily until Day 30 p.i. For treatment with Ang-1, mice were intraperitoneally injected with 1μg of rhAng-1 (R&D Systems)(dissolved in 100 μL phosphate-buffered saline per injection) or the same volume of control buffer (100 μL phosphate-buffered saline per injection) [10]. "
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    • "COMP-Angpt-1 LPS Ameliorated leukocyte adhesion Standard 2009 Kim et al., 2009 COMP-Angpt-1 LPS Protects against acute kidney injury Standard 2010 Tabruyn et al., 2010 Angpt-2 inhibition M. pulmonis Reduced local inflammation Standard 2011 David et al., 2011b rhAngpt-1 i.v. CLP Improved survival, better organ function Standard 2011 Kumpers et al., 2011 Tie2 agonist CLP Improved survival, better organ function Standard 2011 David et al., 2011a Tie2 agonist LPS Improved leakage, organ function, survival Standard 2012 Ghosh et al., 2012 Angpt-2 +/2 / Ad Angpt-1 Anthrax Improved leakage, organ function, survival Standard 2012 Kurniati et al., 2012 Angpt-2(2/2) LPS Worse kidney function Alternative 2012 Tzepi et al., 2012 rhAngpt-2 PSA sepsis Improved survival Alternative 2012 David et al., 2012 Angpt-2 (+/2) CLP/LPS Improved organ function and survival Standard Ad, adenovirus; Angpt, angiopoietin; CLP, cecal ligation and puncture; COMP, cartilage oligomeric matrix protein; KO, knockout; LPS, lipopolysaccharide; M. pulmonis, Mycoplasma pulmonis; PSA, pseudomonas aeruginosa; rhAngpt, recombinant human angiopoietin; TNFa, tumor necrosis factor a; VEGF, vascular endothelial growth factor. "
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