Published ahead of print on April 30, 2003, doi:10.1164/rccm.200209-1051OC Am. J. Respir. Crit. Care Med., Volume 168, Number 1, July 2003, 85-91 A more recent version of this article appeared on July 1, 2003
Submitted on September 17, 2002 Beta-lapachone reduces endotoxin-induced macrophage activation and lung edema and mortalityHuei-Ping Tzeng1,1 Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, 2 Nursing, Chung-Tai Institute of Health Sciences and Technology, Taichung, Taiwan * To whom correspondence should be addressed. E-mail: shliu{at}ha.mc.ntu.edu.tw.
Beta-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 beta-lapachone on lipopolysaccharide-induced responses in rat alveolar macrophages, and to evaluate its in vivo anti-inflammatory effect. A significant increase in nitrite production and inducible nitric oxide synthase expression was elicited in macrophages treated with lipopolysaccharide that was inhibited by co-incubation with beta-lapachone. Beta-lapachone could also inhibit the production of tumor necrosis factor-alpha induced by lipopolysaccharide. Lipopolysaccharide induces protein tyrosine phosphorylation and nuclear factor kappaB binding activity by gel mobility shift assay in macrophages. These events were significantly inhibited by beta-lapachone. Furthermore, beta-lapachone in vivo protected against the induction of lung edema, lung inducible nitric oxide synthase protein expression and nuclear factor kappaB activation, lethality, and increased plasma nitrite and serum tumor necrosis factor-alpha levels induced by lipopolysaccharide. These results indicate that beta-lapachone suppresses inducible nitric oxide synthase induction and tumor necrosis factor-alpha production mediated by the inhibition of protein tyrosine phosphorylation and nuclear factor kappaB activation caused by lipopolysaccharide. This results in a beneficial effect in an animal model of sepsis. Key words: beta-lapachone; inducible nitric oxide synthase; tumor necrosis factor-alpha; nuclear factor kappaB; protein tyrosine phosphorylation
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