title: Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis.
abstract: OBJECTIVE
  Angiopoietin-2, a protein secreted by stimulated endothelium and an antagonist of the endothelium-stabilizing receptor Tie2, contributes to the pathophysiology of septic multiple organ dysfunction. We tested the therapeutic potential of a pulmonary-endothelium-specific RNA interference-based angiopoietin-2 targeting strategy in sepsis.
  
  
  METHODS
  Laboratory and animal research.
  
  
  METHODS
  Research laboratories of the Medical School Hannover, Department of Nephrology and Hypertension, Hannover and Silence Therapeutics GmbH, Berlin.
  
  
  METHODS
  C57Bl/6 mice.
  
  
  METHODS
  Lung-endothelium-specific angiopoietin-2 small interfering RNA was administered both before and after sepsis induction (cecal ligation and puncture or lipopolysaccharides) intravenously.
  
  
  RESULTS
  Angiopoietin-2 small interfering RNA was highly specific and reduced angiopoietin-2 expression in the septic murine lungs up to 73.8% (p = 0.01) and enhanced the phosphorylation of Tie2 both in control and septic animals. Angiopoietin-2 small interfering RNA reduced pulmonary interleukin-6 transcription, intercellular adhesion molecule expression, neutrophil infiltration, and vascular leakage. Manifestations of sepsis were also attenuated in distant organs, including the kidney, where renal function was improved without affecting local angiopoietin-2 production. Finally, angiopoietin-2 small interfering RNA ameliorated the severity of illness and improved survival in cecal ligation and puncture, both as a pretreatment and as a rescue intervention.
  
  
  CONCLUSIONS
  The Tie2 antagonist angiopoietin-2 represents a promising target against sepsis-associated multiple organ dysfunction. A novel RNA interference therapeutic approach targeting gene expression in the pulmonary endothelium could be a clinically relevant pharmacological strategy to reduce injurious angiopoietin-2 synthesis.
authors.affiliation: 1Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany. 2Silence Therapeutics GmbH, Berlin, Germany. 3Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stiehl
authors.forename: Kristina
authors.initials: K
authors.lastname: Thamm
authors.forename: Jörg
authors.initials: J
authors.lastname: Kaufmann
authors.forename: Ute
authors.initials: U
authors.lastname: Schaeper
authors.forename: Torsten
authors.initials: T
authors.lastname: Kirsch
authors.forename: Hermann
authors.initials: H
authors.lastname: Haller
authors.forename: Ansgar
authors.initials: A
authors.lastname: Santel
authors.forename: Chandra C
authors.initials: CC
authors.lastname: Ghosh
authors.forename: Samir M
authors.initials: SM
authors.lastname: Parikh
authors.forename: Sascha
authors.initials: S
authors.lastname: David
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology
chemical_list: D042702:Angiopoietin-2; D034741:RNA, Small Interfering; D042787:Receptor, TIE-2; C079086:Tek protein, mouse