Lung-Targeted RNA Interference Against Angiopoietin-2 Ameliorates Multiple Organ Dysfunction and Death in Sepsis

Authors:
  • KTKristina Thamm
    Kristina Thamm
  • JKJörg Kaufmann
    Jörg Kaufmann
  • USUte Schaeper
    Ute Schaeper
  • HHHermann Haller
    Hermann Haller
  • ASAnsgar Santel
    Ansgar Santel
  • CGChandra C. Ghosh
    Chandra C. Ghosh
  • SPSamir M. Parikh
    Samir M. Parikh
  • SDSascha David
    Sascha David
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Abstract
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. Laboratory and animal research. Research laboratories of the Medical School Hannover, Department of Nephrology and Hypertension, Hannover and Silence Therapeutics GmbH, Berlin. C57Bl/6 mice. Lung-endothelium-specific angiopoietin-2 small interfering RNA was administered both before and after sepsis induction (cecal ligation and puncture or lipopolysaccharides) intravenously. 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. 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.

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