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.

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.

• Authors: Thomas Stiehl, Kristina Thamm, Jörg Kaufmann, Ute Schaeper, Torsten Kirsch, Hermann Haller, Ansgar Santel, Chandra C Ghosh, Samir M Parikh, Sascha David
• Journal: Critical care medicine (Crit Care Med) Vol. 42 Issue 10 Pg. e654-62 (Oct 2014) ISSN: 1530-0293 [Electronic] United States
• PMID: 25083983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiopoietin-2
• RNA, Small Interfering
• Receptor, TIE-2
• Tek protein, mouse

Topics

• Angiopoietin-2 (metabolism, physiology)
• Animals
• Disease Models, Animal
• Inflammation (etiology, metabolism, physiopathology)
• Lung (metabolism)
• Mice
• Mice, Inbred C57BL
• Multiple Organ Failure (etiology, metabolism, physiopathology)
• RNA Interference (physiology)
• RNA, Small Interfering (metabolism)
• Receptor, TIE-2 (metabolism)
• Sepsis (complications, metabolism, mortality, physiopathology)