Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis

Thomas Stiehl, Kristina Thamm, Jörg Kaufmann, Ute Schaeper, Torsten Kirsch, Hermann Haller, Ansgar Santel, Chandra C. Ghosh, Samir M. Parikh, Sascha David

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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 pulmonaryendothelium-specific RNA interference-based angiopoietin-2 targeting strategy in sepsis.

Design: Laboratory and animal research. Settings: Research laboratories of the Medical School Hannover, Department of Nephrology and Hypertension, Hannover and Silence Therapeutics GmbH, Berlin. Subjects: C57Bl/6 mice. Interventions: Lung-endothelium-specific angiopoietin-2 small interfering RNA was administered both before and after sepsis induction (cecal ligation and puncture or lipopolysaccharides) intravenously. Measurements and Main 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)e654-e662
JournalCritical care medicine
Volume42
Issue number10
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Angiopoietin-2
  • Endothelium
  • Permeability
  • RNA interference
  • Sepsis
  • Small interfering RNA
  • Tie2

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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