Nitric oxide ameliorates TNF-a or endotoxin/actinomycin D-induced apoptosis.

用一氧化氮(NO)产生化合物治疗肿瘤坏死因子-α(TNF-α)和放线菌素D诱导的L929细胞的凋亡，这是由细胞外低分子DNA泄漏引起的亚G1峰的出现所确定的。NO还阻止了由肿瘤坏死因子-α(TNF-α)和放线菌素D诱导的活性氧中间产物的产生，通过脱氢罗丹明123和氢乙胺的氧化来评估。由于鱼藤酮或抗霉素A对线粒体呼吸的抑制抑制了二氢罗丹明123和氢乙啶的氧化增加，提示肿瘤坏死因子-α加速了线粒体电子传递系统中的活性氧中间产物的泄漏。这些结果表明，NO给药后减少线粒体中活性氧中间产物的形成可能部分地阻止了肿瘤坏死因子-α和放线菌素D诱导的细胞凋亡。代谢抑制剂放线菌素D阻断了大部分内毒素诱导的血浆亚硝酸盐/硝酸盐水平的升高，一氧化氮合酶抑制剂的应用也促进了内毒素诱导的体内肝损伤。给予氧化亚氮供体后，小鼠血浆亚硝酸盐/硝酸盐水平升高，放线菌素D/脂多糖诱导的肝损伤减轻。这些结果表明，一氧化氮可能调节肝脏的程序性细胞死亡，诱导包括诱导型一氧化氮合酶在内的基因在保护肝脏免受内毒素诱导的细胞凋亡损伤中起重要作用。这种作用似乎至少部分是通过可溶性鸟苷途径来实现的。

'Treatment with the nitric oxide (NO)-generating compound prodtected cultured L929 cells from apoptosis induced by tumor necrosis factor-alpha (TNF-alpha) plus actinoinycin D,as determined by the appearance of a sub-Gl peak caused by extracellular leakage of low molecular weight DNA.NO also prevented TNF-alpha plus actinomycin D-induced enhancement of the production of reactive oxygen intermediates, as assessed by oxidation of both dehydrorhodamine 123 and hydroethidine. Because inhibition of mitochondrial respiration by rotenone or antimycin A suppressed the increase of oxidation of both dihydrorhodamine 123 and hydroethidine, it was suggested that TNF-alpha accelerated the leakage of reactive oxygen intermediates from the mitochondria electron transport system. These findings indicate that decrease mitochondria formation of ractive oxygen intermediates after NO administration might partly prevent TNF-alpha plus actinomycin D induced apoptosis.The metabolic inhibitor actinomycin D blocked most of the LPS-induced rise of plasma nitrite/nitrate levels, as did administration of a nitric oxide synthase inhibitor which also promoted LPS-induced apoptotic liver damage in vivo. Administration of nitoric oxide donors to mice resulted in elevation of the plasma nitrite/nitrate level and amelioration of actinomycin D/LPS-induced apoptotic liver damage. These results suggested that nitric oxide may regulated programmed cell death in the liver and that induction of genes including inducible nitric oxide synthase plays an important role in protecting the liver against LPS-induced apoptotic damage. This effect appears to be mediated, at least in part, by the soluble guanylate pathway.