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Original Article

Nuclear Factor-B Decoy Oligodeoxynucleotides Prevent Acute Lung Injury in Mice with Cecal Ligation and Puncture-Induced Sepsis

Departments of Pharmacology (Y.H.) and Anesthesiology and Critical Care Medicine (N.M., S.J., S.G.), Hokkaido University Graduate School of Medicine, Sapporo, Japan

Abstract

The transcription factor nuclear factor-B (NF-B) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-B sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-B decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-B decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H₁-receptor, platelet-activating factor receptor, and bradykinin B₁ and B₂ receptors in lung Histological damage in lungs tissues. (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-B decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-B decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.

Received for publication August 5, 2004.

Accepted for publication December 1, 2004.

Address correspondence to: Dr. Yuichi Hattori, Department of Pharmacology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. E-mail: yhattori{at}med.hokudai.ac.jp

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