Targeting host E-selectin expression by antisense oligodeoxynucleotides as potential antiendotoxin therapy in vivo.
This study sought to determine if antisense oligodeoxynucleotides would inhibit E-selectin expression, which mediates leukocyte adhesion on endothelial cells, otherwise induced by in vivo endotoxin challenge. Six antisense phosphorothioate oligodeoxynucleotides calculated to bind porcine E-selectin mRNA were tested in porcine aortic endothelial cells. One, ISIS9481, exerted significant inhibition of E-selectin expression induced by tumor necrosis factor-α + endotoxin [lipopolysaccharide (LPS)]. Pigs were challenged with LPS (10 μg/kg) and treated with ISIS9481 (10 mg/kg) (n = 6). Two control groups were used, an antisense inactive in porcine aortic endothelial cells (n = 6) and saline (n = 5), and were combined as control (C = 11). Control pigs challenged with LPS expressed E-selectin in heart, lung, kidneys, and liver, whereas antisense-treated pigs expressed little E-selectin in these tissues. Cardiovascular data indicated that antisense treatment attenuated pathophysiological alterations induced by LPS. Specifically, in control pigs, LPS reduced cardiac output 32% from baseline, increased pulmonary (+116%) and systemic vascular resistances (+16%), and generated neutropenia (from 51,000 at basal to 18,000 polymorphonuclear neutrophils (PMN)/μL after LPS). In antisense-treated pigs, cardiac output decreased only 18%, pulmonary vascular resistance remained unchanged, whereas systemic vascular resistance decreased compared with basal values (-37%). PMN counts remained at 45,000-54,000/μL at 3-4 hours after LPS. These data demonstrate that antisense oligodeoxynucleotides, designed and tested in vitro to interact with 1 gene product, can be developed as either therapeutics or experimental tools in vivo.
Goldfarb
Roy D
RD
Department of Cardiology, Cooper University Hospital , Camden, NJ, USA. goldfard@umdnj.edu
Bennett
C Frank
CF
Butler
Madeline
M
Condon
Thomas
T
Parrillo
Joseph E
JE
D000818:Animals; D001011:Aorta / Q000166:cytology; D019040:E-Selectin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000627:therapeutic use*; D018805:Sepsis / Q000517:prevention & control; D013552:Swine
D019040:E-Selectin; D008070:Lipopolysaccharides; D020319:Oligodeoxyribonucleotides, Antisense