Yao Yong-ming, Xu Cai-lin, Yao Feng-hua, Yu Yan, Sheng Zhi-yong
Burn Institute, First Hospital Affiliated to the PLA General Hospital, Beijing, China.
Zhonghua Shao Shang Za Zhi. 2006 Dec;22(6):405-10.
To investigate the pattern of nuclear factor-kappaB (NF-kappaB) activation in rats with lipopolysaccharide( LPS) shock, and to explore the mechanism of NF-kappaB signal pathway in the biopterin-mediated nitric oxide(NO) induction, as well as its role in the development of multiple organ dysfunction syndrome ( MODS) secondary to endotoxin challenge.
Fourty-seven male Wistar rats were randomly divided into control group ( C, n = 8) , LPS group ( n = 24, with 8 rats at each time-points, and shock model was made by injection of same dosage of LPS) , and pyrrolidine dithiocarbamate (PDTC) treatment group ( PDTC, n = 15, with 5 rats at each time-points, and the rats were injected with LPS and PDTC). The rats were sacrificed at 2,6,12 post-injection hour( PIH) , and the blood and tissue samples from liver, lungs and kidneys were harvested for the determination of NF-KB activity, GTP cyclohydrolase I (GTP-CH I ) , and inducible nitric oxide synthase (iNOS) mRNA expression in the liver, lungs and kidneys, plasma and tissue content of biopterin and NO, as well as hepatic and renal function, and pulmonary myeloperoxidase activity.
NF-kappaB DNA binding activity in LPS group was rapidly enhanced in liver, lungs and kidneys after endotoxin challenge when compared with that in controls (e. g. in pulmonary tissue it was 26+/-6) , and it reached the peak at 2 PIH, which was 291 +/-44 in pulmonary tissue( P <0. 01). GTP-CH I mRNA expression and biopterin levels in the liver, lung and kidney of each group were obviously higher than those in control group( P <0.05 or 0.01) , and it maintained at high levels at 12 PIH. Additionally, different degrees of dysfunction of the above mentioned organs was observed. Treatment with PDTC, an inhibitor of NF-KB signal transduction pathway, could reduce NF-kappaB DNA binding activity, inhibit GTP-CH I and iNOS/NO mRNA expression, as well as BH4, and NO levels in various tissues. Meanwhile the multiple organ damage was significantly ameliorated by PDTC pretreatment.
Endotoxin challenge can rapidly lead to activation of NF-kappaB in various tissues, and NF-KB pathway might markedly up-regulate the production of biopterin/NO following endotoxic shock. Inhibition of NF-kappaB pathway attenuates inflammatory response and ameliorates multiple organ dysfunction, which might be associated with its down-regulation of the excessive activation of iNOS mediated by biopterin.
研究脂多糖（LPS）休克大鼠核因子-κB（NF-κB）的激活模式，探讨NF-κB信号通路在生物蝶呤介导的一氧化氮（NO）诱导中的机制及其在内毒素攻击继发多器官功能障碍综合征（MODS）发生发展中的作用。
47只雄性Wistar大鼠随机分为对照组（C组，n = 8）、LPS组（n = 24，每个时间点8只，通过注射相同剂量的LPS制备休克模型）和吡咯烷二硫代氨基甲酸盐（PDTC）治疗组（PDTC组，n = 15，每个时间点5只，大鼠注射LPS和PDTC）。在注射后2、6、12小时处死大鼠，采集血液以及肝、肺、肾组织样本，测定肝、肺、肾组织中NF-κB活性、鸟苷三磷酸环化水解酶I（GTP-CH I）和诱导型一氧化氮合酶（iNOS）mRNA表达，血浆和组织中生物蝶呤和NO含量，以及肝肾功能和肺髓过氧化物酶活性。
与对照组相比，LPS组内毒素攻击后肝、肺、肾组织中NF-κB DNA结合活性迅速增强（如肺组织中为26±6），在注射后2小时达到峰值，肺组织中为291±44（P <0.01）。各组肝、肺、肾组织中GTP-CH I mRNA表达和生物蝶呤水平均明显高于对照组（P <0.05或0.01），并在注射后12小时维持在高水平。此外，观察到上述器官不同程度的功能障碍。用NF-κB信号转导通路抑制剂PDTC治疗可降低NF-κB DNA结合活性，抑制GTP-CH I和iNOS/NO mRNA表达，以及生物蝶呤和NO在各种组织中的水平。同时，PDTC预处理可显著改善多器官损伤。
内毒素攻击可迅速导致各组织中NF-κB激活，NF-κB通路可能在内毒素休克后显著上调生物蝶呤/NO的产生。抑制NF-κB通路可减轻炎症反应并改善多器官功能障碍，这可能与其下调生物蝶呤介导的iNOS过度激活有关。
