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ß-Lapachone Reduces Endotoxin-induced Macrophage Activation and Lung Edema and Mortality

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei; and Department of Nursing, Chung-Tai Institute of Health Sciences and Technology, Taichung, Taiwan

Correspondence and requests for reprints should be addressed to Shing-Hwa Liu, Ph.D., Institute of Toxicology, College of Medicine, National Taiwan University, Number 1, Jen-Ai Road, Section 1, Taipei 10043, Taiwan. E-mail: shliu{at}ha.mc.ntu.edu.tw

ß-Lapachone, a 1,2-naphthoquinone, is a novel chemotherapeutic agent. It has been shown to be capable of suppressing inducible nitric oxide synthase expression and function in rat alveolar macrophages. The authors further performed experiments to examine the molecular mechanism of ß-lapachone on LPS-induced responses in rat alveolar macrophages and to evaluate its in vivo antiinflammatory effect. A significant increase in nitrite production and inducible nitric oxide synthase expression was elicited in macrophages treated with LPS that was inhibited by coincubation with ß-lapachone. ß-Lapachone could also inhibit the production of tumor necrosis factor- induced by LPS. LPS induces protein tyrosine phosphorylation and nuclear factor-B binding activity by gel mobility shift assay in macrophages. These events were significantly inhibited by ß-lapachone. Furthermore, ß-lapachone in vivo protected against the induction of lung edema, lung-inducible nitric oxide synthase protein expression and nuclear factor-B activation, lethality, and increased plasma nitrite and serum tumor necrosis factor- levels induced by LPS. These results indicate that ß-lapachone suppresses inducible nitric oxide synthase induction and tumor necrosis factor- production mediated by the inhibition of protein tyrosine phosphorylation and nuclear factor-B activation caused by LPS. This results in a beneficial effect in an animal model of sepsis.

Key Words: ß-lapachone • inducible nitric oxide synthase • tumor necrosis factor- • nuclear factor-B • protein tyrosine phosphorylation

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