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B on septic lung in mice
1 Department of Anesthesiology & Critical Care Medicine, Hokkaido Universiry Graduate School of Medicine, Sapporo, Japan
2 Department of Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
3 Department of Biochemistry, Hokkaido University Graduate School of Medicine, Sapporo, Japan
4 Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
* To whom correspondence should be addressed. E-mail: yhattori{at}med.hokudai.ac.jp.
Nuclear factor-
B (NF-B) plays a key role in regulating expression of several genes involved in the pathophysiology of endotoxic shock. We investigated whether in vivo introduction of synthetic double-stranded DNA with high affinity for the NF-B binding site could block expression of genes mediating pulmonary vascular permeation and thereby provide effective therapy for septic lung failure. Endotoxin shock was induced by an intravenous injection of 10 mg/kg Escherichia coli endotoxin in mice. NF-B decoy oligodeoxynucleotide (ODN) was introduced in vivo 1 h after endotoxin by using a gene transfer kit. At 10 h the blood samples were collected for measurement of histamine and blood gas analysis. The gene and protein expression levels of target molecules were determined by means of Northern and Western blot analysis, respectively. The transpulmonary flux of [125I]albumin was used as an index of lung vascular permeability. Administration of endotoxin caused marked increases in plasma histamine and gene and protein expressions of histidine decarboxylase, histamine H1-receptors and inducible nitric oxide synthase in lung tissues. Elevated lung vascular permeability was also found. Blood gas analysis showed concurrent decreases in arterial PO2, PCO2, and pH. All these events induced by endotoxin were significantly inhibited by transfection of NF-B decoy ODN, but not by its mutated (scrambled) form used as a control. Our results indicate for the first time the potential usefulness of NF-B decoy ODN for gene therapy of endotoxic shock.
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