Lung-targeted RNA interference against angiopoietin-2 ameliorates multiple organ dysfunction and death in sepsis.
Crit Care Med
; 42(10): e654-62, 2014 Oct.
Article
em En
| MEDLINE
| ID: mdl-25083983
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 MAINRESULTS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
Interferência de RNA
/
Angiopoietina-2
/
Pulmão
/
Insuficiência de Múltiplos Órgãos
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Crit Care Med
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Marrocos