The contribution of nitric oxide to the paraquat-induced cell injury.

本研究首先研究了百草枯（PQ）对培养的A549肺腺癌细胞一氧化氮（NO）生物合成的影响。PQ与细胞因子的组合协同增加了亚硝酸盐的量，作为NOS活性的指标，其抑制了诱导型NO合酶（iNOS）mRNA的表达。此外，这种内源性NO显示出对PQ中毒的保护作用，而更大量的外源性NO刺激细胞损伤，可能是因为与PQ衍生的超氧化物相互作用。研究了亚致死量和致死量百草枯暴露对大鼠肝、肾和肺组织中诱导型一氧化氮合酶（iNOS）和白细胞介素（IL）-1 β基因表达的影响。肾和肺的iNOS信号不受影响，但在肝脏中观察到明显的抑制，然后显着刺激的信号暴露于致死剂量。然而，肝脏中的IL-1 β信号在整个实验中下降，表明暴露于致死剂量的肝脏iNOS表达的变化与IL-1 β无关。在致死剂量组中，肾脏中IL-1 β信号在1小时达到峰值，3小时下降，而肺中IL-1 β信号在整个实验期间增加。这些结果表明，PQ有一个直接的双相效应在体内肝脏中的诱导型一氧化氮合酶的表达，从而提供了可能参与PQ诱导的损伤的一氧化氮的产生的证据。另一方面，他们也表明，肺，最严重的影响器官，可能是由IL-1 β或其他促炎细胞因子，而不是NO调节。

In the present study, we first investigated the effect of paraquat (PQ) on nitric oxide (NO) biosynthesis in cultured A549 lung adenocarcinoma cells. A combination of PQ with cytokines synergistically increased the amount of nitrite, as an index of NOS activity, which paralleled the expression of inducible NO synthase (iNOS) mRNA.In addition, this endogenous NO showed a protective effect against PQ poisoning, while larger exogenous amounts of NO stimulated cell injury, probably because of interaction with superoxide derived from PQ.Next, using RT-PCR,we studied the effect of sub-lethal and lethal paraquat exposure on iNOS and interleukin (IL)-1beta gene expression in rat liver, kidney and lung. The iNOS signals in kidney and lung were unaffected, but a marked suppression and then a significant stimulation of the signals was observed in liver exposed to a lethal dose. The IL-1beta signal in liver, however, decreased throughout the experiment, suggesting that the changes in liver iNOS expression exposed to a lethal dose was not relevant to IL-1beta. In the lethal dose group, the IL-1beta signal in kidney reached a peak at 1 hr, declining by 3 hr, whereas that in lung increased throughout the experiment. These results demonstrate that PQ has a direct biphasic effect on iNOS expression in liver in vivo, thus providing evidence of possible involvement of nitric oxide generation in PQ-induced injury. On the other hand, they also indicate that the lung, the most severely affected organ, may be regulated by IL-1beta or other proinflammatory cytokines and not by NO.