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

本文研究了一氧化氮合酶抑制剂对日本血吸虫感染小鼠的作用。令人惊讶地发现，口服NOS抑制剂L-NAME及其无活性对映体D-NAME对感染6周时处死小鼠的蠕虫负荷具有显著降低作用，并且D-NAME在C57 BL/6小鼠中比L-NAME更有效。在详细的给药方案研究中，当给予50- 100 mg/ml浓度时显示出显著的作用，而更高浓度（200或400 mg/ml）没有明显的作用。在感染后3 ~ 42天给药，连续6天在感染后14-24天给药，保护作用明显。在使用几种细胞因子缺陷小鼠时，有趣的是，对映异构体的作用随每种品系而不同。D-NAME在IFN-γ KO小鼠中是有效的，而在IL-4和IL-13 KO小鼠中L-NAME显示出效果。血清NO水平的测定表明，在D-NAME组中，C57 BL/6的NO水平升高，而在L-NAME组中，NO水平降低。而IL-13基因敲除小鼠的NO水平与L-NAME呈负相关。免疫组化结果显示，IL-10水平呈下降趋势，而IFN-γ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保护作用。总之，我们目前的研究表明，NOS抑制剂在感染性疾病的防御机制的几个有趣的方面。

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.