title: Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis.
abstract: BACKGROUND
  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.affiliation: Department of Nephrology & Hypertension, Hannover Medical School, Carl-NeubergStrasse1, D- 30625, Hannover, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: David
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Matijs van
authors.initials: Mv
authors.lastname: Meurs
authors.forename: Jan G
authors.initials: JG
authors.lastname: Zijlstra
authors.forename: Christian
authors.initials: C
authors.lastname: Koenecke
authors.forename: Claudia
authors.initials: C
authors.lastname: Schrimpf
authors.forename: Nelli
authors.initials: N
authors.lastname: Shushakova
authors.forename: Faikah
authors.initials: F
authors.lastname: Gueler
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Philipp
authors.initials: P
authors.lastname: Kümpers
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009102:Multiple Organ Failure / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use*; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D015996:Survival Rate
chemical_list: D042683:Angiopoietin-1; D042702:Angiopoietin-2; D011994:Recombinant Proteins; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse