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


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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    • "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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    ABSTRACT: Sepsis is a systemic inflammatory response to infection. A common end-feature these patients regularly suffer from is the so-called multiple organ dysfunction syndrome, an often fatal consequence of organ hypo-perfusion, coagulopathy, immune dysregulation, and mitochondrial dysfunction. Microvascular dysfunction critically contributes to the morbidity and mortality of this disease. The angiopoietin (Angpt)/Tie2 system consists of the transmembrane endothelial tyrosine kinase Tie2 and its circulating ligands (Angpt1, 2 and 3/4). The balance between the canonical agonist Angpt-1 and its competitive inhibitor Angpt-2 regulates basal endothelial barrier function, and the leakage and vascular inflammation that develop in response to pathogens and cytokines. Here we summarize recent work in mice and men to highlight the therapeutic potential in this pathway to prevent or even reverse microvascular dysfunction in this deadly disease.
    Journal of Pharmacology and Experimental Therapeutics 02/2013; 345(1). DOI:10.1124/jpet.112.201061 · 3.97 Impact Factor
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    • "Recent studies have shown that Ang-1 can improve cardiac function after myocardial ischemic injury [19] and sepsis and septic shock [20] . It has been previously reported that overexpression of Ang-1 significantly reduces myocardial infarction after myocardial ischemia injury and protects cardiac myocytes against oxidative stress-induced apoptosis [21] . "
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    ABSTRACT: Doxorubicin (Dox) is a major anticancer chemotherapeutic agent. However, it causes cardiomyopathy due to the side effect of cardiomyocyte apoptosis. We have previously reported that angiopoietin-1 significantly reduced myocardial infarction after ischemic injury and protected cardiomyocytes from oxidative stress-induced apoptosis. It is hypothesized that angiopoietin-1 may protect cardiomyocytes from Dox-induced apoptosis. Cardiomyocytes H9C2 were transfected with adenovirus expressing angiopoietin-1 (Ad5-Ang-1) 24 h before the cells were challenged with Dox at a concentration of 2 µmol/L. Ad5-GFP served as the vector control. Cardiomyocyte apoptosis was evaluated using Annexin V-FITC staining and caspase-3 and caspase-8 activity was determined by Western blotting. The results showed that Dox treatment significantly induced cardiomyocyte apoptosis as evidenced by the greater number of Annexin V-FITC stained cells and increases in caspase-3 and caspase-8 activity. In contrast, overexpression of angiopoietin-1 significantly prevented Dox-induced cardiomyocyte apoptosis. To elucidate the mechanisms by which angiopoietin-1 protected cells from Dox-induced apoptosis, we analyzed both extrinsic and intrinsic apoptotic signaling pathways. We observed that angiopoietin-1 prevented Dox-induced activation of both extrinsic and intrinsic apoptotic signaling pathways. Specifically, angiopoietin-1 prevented DOX-induced increases in FasL and Bax levels and cleaved caspase-3 and caspase-8 levels in H9C2 cells. In addition, overexpression of angiopoietin-1 also activated the pro-survival phosphoinositide-3 kinase (PI3K)/Akt signaling pathway and decreased Dox-induced nuclear factor-kappaB (NF-κB) activation. Our data suggest that promoting the expression of angiopoietin-1 could be a potential approach for reducing Dox-induced cardiomyocyte cytoxicity.
    11/2012; 26(6):432-8. DOI:10.7555/JBR.26.20120006
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    • "Cartilage oligomeric matrix protein-angiopoietin-1 (COMP.Ang-1) is a soluble and stabilized variant that binds more avidly to Tie-2 than native Ang-1 [12]. COMP.Ang-1, adenovirus-delivered Ang-1, recombinant human Ang-1, cell-based therapies, and a synthetic Tie-2 agonist all reduce vascular leak and end-organ dysfunction in murine sepsis models [13-19]. Each of these approaches has some appeal; Alfieri and colleagues chose to investigate the effects of a modified Ang-1 molecule, MAT.Ang-1, formed by fusing the coiled-coil domain of human matrilin-1 to the fibrinogen-like domain of human Ang-1. "
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    ABSTRACT: Angiopoietin-1 is a Tie-2 receptor agonist that stabilizes vascular endothelium, promoting endothelial maturation and preventing capillary leak. Angiopoietin-2 is largely a competitive partial antagonist that is markedly elevated in humans and animal models of sepsis and other inflammatory states, directly disrupts the endothelial barrier, and has been correlated with end-organ dysfunction and death in sepsis. In the previous issue of Critical Care, Alfieri and colleagues used intravital microscopy to study the microvasculature in a murine model of sepsis. Treatment with a modified angiopoietin-1 molecule led to reversal of albumin vascular leak and improved blood flow to skeletal muscle, as well as a decrease in the levels of several inflammatory cytokines. Importantly, the angiopoietin-1 variant was administered 20 hours after initial lipopolysaccharide challenge. This study adds to the evidence that the angiopoietin/Tie-2 axis represents a modifiable pathway through which targeted therapy may be able to directly reverse part of the pathology of sepsis.
    Critical care (London, England) 10/2012; 16(6):177. DOI:10.1186/cc11829 · 4.48 Impact Factor
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