Killing of Schistosoma japonicum in the administration of NOS inhibitors and its mechanism

研究了一氧化氮合酶抑制剂对日本血吸虫感染小鼠的影响。令人惊讶的是，口服一氧化氮合酶抑制剂L-NAME及其灭活对映体D-NAME对感染6周的小鼠有显著的减虫作用，并且D-NAME对C57BL/6小鼠的作用比L-NAME更有效。在对D-NAME给药程序的详细研究中，当给药浓度为50-100 mg/ml时，效果显著，而较高浓度，200或400 mg/ml，则没有明显效果。感染后3~42d给药时间观察表明，在感染后14~24d内连续给药6d，保护作用明显。在使用几种细胞因子缺陷小鼠时，有趣的是，对映体的效果因品系不同而不同。D-NAME对干扰素-gKO小鼠有效，而对IL-4和IL-13KO小鼠有作用，L-NAME对干扰素-g KO小鼠有作用。血清NO水平测定显示，D-NAME组C57BL/6小鼠NO水平升高，而L-NAME组NO水平下降。在IL-13KO小鼠中，NO含量与L的名字呈正相关，呈上升趋势。细胞因子分析显示，保护性小鼠脾细胞IL-10水平有下降趋势，而干扰素-g水平无明显变化。这些观察结果有力地表明，NO在日本血吸虫感染中起到保护作用。总体而言，我们目前的研究表明，一氧化氮合酶抑制剂在传染病防御机制中有几个有趣的方面。

The effect of nitric oxydase synthase inhibitors in Schistosoma japonicum-infected mice was studied. It was surprisingly found that oral administration of NOS inhibitors, L-NAME and its inactive enantiomer D-NAME, had significant decreasing effects on the worm burden when mice were scarified at 6 week of infection and that D-NAME was more effective than L-NAME in C57BL/6 mice in comprison. In detailed study of D-NAME administration schedules, significant effects were shown when 50-100mg/ml concentration were given, whereas higher concentrations, 200 or 400mg/ml, had no apparent effects. The time of administration examined between 3 to 42 day of infection indicated that the protective effects were apparent when the inhibitor was given during 14-24 day of infection for consecutive 6 days. In the use of several cytokine deficient mice, the effect of the enantiomers interestingly differed with each strain. D-NAME was effective in IFN-g KO mice, while in IL-4 and IL-13KO mice L-NAME showed the effect. Measurement of serum NO levels showed that there was increase in NO in D-NAME-administered C57BL/6, while decreased NO was seen in the administration of L-NAME. In IL-13 KO mice there was exactly reverse relationship, showing increase in NO with L-NAME. Cytokine analysis of splenic cells in protective mice showed a tendency of decrease in IL-10 level, while there was no significant changes in IFN-g level. These observations strongly suggests NO plays a protective role in S.japonicum infection. In whole, our present study indicates several interesting aspects of NOS inhibitors in defensive mechanism of infectious disease.