Article

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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    Full-text · Article · Feb 2016 · PLoS ONE
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    • "Ang-1 takes part in maintaining endothelial integrity and inhibiting inflammation while Ang-2 promotes endothelial leak. Furthermore, treatments targeted in animal models of sepsis to block angio- poietin-2, or enhance angiopoietin-1 have been shown to be protective [29,464748. We and others have shown in smaller studies that the Ang-1/Ang-2 axis is implicated in sepsis pathogenesis and associated with poor outcomes [23,25,49]. "
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    Full-text · Article · Oct 2015 · PLoS ONE
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    • "It is anticipated that novel pre-analytical approaches and further advancement in epigenetic platforms as well as single-cell analysis will enable transcriptional and epigenetic studies of genes whose expression is not as markedly altered in whole tissue samples. Sepsis-induced reductions of angiogenic protein levels have previously been reported in the lung [46, 48, 49], kidney [50, 51], and liver [46] . Similar observations were made for sepsis downregulation of Kdr protein in the lung [45, 52]. "
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    Full-text · Article · May 2015 · Critical care (London, England)
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