beta-Lapachone reduces endotoxin-induced macrophage activation and lung edema and mortality.
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 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 beta-lapachone. beta-Lapachone could also inhibit the production of tumor necrosis factor-alpha induced by LPS. LPS 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 LPS. 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 LPS. This results in a beneficial effect in an animal model of sepsis.
Institute of Toxicology, College of Medicine, National Taiwan University, Number 1, Jen-Ai Road, Section 1, Taipei 10043, Taiwan.
Huei-Ping
HP
Tzeng
Feng-Ming
FM
Ho
Kuo-Fang
KF
Chao
Min-Liang
ML
Kuo
Shoei-Yn
SY
Lin-Shiau
Shing-Hwa
SH
Liu
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004731:Endotoxins / Q000009:adverse effects*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000009:adverse effects*; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology; D009285:Naphthoquinones / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation; D011654:Pulmonary Edema / Q000382:microbiology* / Q000401:mortality / Q000517:prevention & control*; D051381:Rats; D018805:Sepsis / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D000890:Anti-Infective Agents; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009285:Naphthoquinones; D014409:Tumor Necrosis Factor-alpha; C014638:beta-lapachone; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases