Effect of antisense oligonucleotides to nuclear factor-κB on the survival of LPS-induced ARDS in mouse

Hiroki Saitoh, Tohru Masuda, Ye Zhang Xiao, Sanae Shimura, Kunio Shirato

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Because nuclear factor (NF)-κB-regulated cytokines, including tumor necrosis factor-α (TNF-α), from monocytes and macrophages have been implicated in the pathogenesis and development of septic shock and acute respiratory distress syndrome (ARDS), the effect of the antisense oligonucleotide to the p65 subunit of NF-κB on the survival of lipopolysaccharide (LPS)-induced ARDS in BALB/ c mice was examined. None and 70% of the animals died of diffuse hemorrhagic lung edema 1 to 2.5 days after intraperitoneal administration of 10 and 20 mg/kg LPS alone, respectively. Intravenously administered antisense oligonucleotide alone did not produce any significant changes in the behavior or lung histology. After intravenous administration of the anti-sense oligonucleotide, both peripheral blood monocytes and alveolar macrophages in bronchoalveolar lavage fluid were confirmed to contain sufficiently large amounts of intracellular antisense oligonucleotides for their function using fluorescein isothiocyanate (FITC)-labeled microscopy. The antisense oligonucleotide administered 6 hours before the intraperitoneal administration of LPS significantly decreased the survival rate with the progress of hemorrhagic edema in lung histology; 90% and 100% of animals treated with the antisense oligonuleotide died 0.5 to 1.5 days after the administration of 10 and 20 mg/kg LPS, respectively. These findings suggest that the suppression of cytokines and mediators in monocytes and alveolar macrophages by the antisense oligonucleotide to the p65 subunit of NF-κB worsens the survival of LPS-induced ARDS in mice with the progress of hemorrhagic lung edema.

Original languageEnglish
Pages (from-to)219-231
Number of pages13
JournalExperimental Lung Research
Volume28
Issue number3
DOIs
Publication statusPublished - 2002 Jan 1

Keywords

  • Alveolar macrophage
  • Cytokoines
  • Lipopolysaccharide-induced ARDS
  • Mouse
  • NF-κB p65 subunit antisense oligonucleotide

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry

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