Treatment of experimental septic shock with microencapsulated antisense oligomers to NF-kappaB

Abstract

NF-kappaB is an ideal target for inhibition of proinflammatory cytokines. The purpose of this study was to determine if microencapsulated antisense oligomer to NF-kappaB can inhibit proinflammatory cytokine release in response to Escherichia coli endotoxin and bacteria. Microencapsulation takes advantage of the phagocytic function of the macrophage to deliver the oligomer intracellularly and enhance the effect. Albumin microcapsules 1 microm in size were prepared by a nebulization method containing antisense oligomers to NF-kappaB. E. coli endotoxin was incubated in 1 ml aliquots of whole blood. Microencapsulated antisense to NF-kappaB was given, and the inhibition of tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, and IL-8 was compared with similar amounts of oligomer in solution. Endotoxic shock was produced in rats using E. coli endotoxin (15 mg/kg). Peritonitis was induced by injecting 10(10) CFU E. coli. Cytokines were measured after simultaneous and delayed (4 h) administration of antisense to NF-kappaB in microcapsules and solution form. TNF was suppressed by 81% in whole blood, 56% in the endotoxic shock model, 89% in the peritonitis model (simultaneous treatment), and 56% in the delayed treatment group. Survival was 70% in the endotoxic shock group, 80% in the simultaneous peritonitis group, and 70% in the delayed treatment group. Microcapsule treatment using antisense to NF-kappaB suppressed TNF and IL-1 levels and mortality significantly better than all solution treatment groups in the whole blood model, endotoxic shock model, and peritonitis model.