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目的探讨内毒素休克动物肝、肺、肾等重要器官生物喋呤(BH4)变化规律及其与多器官损害的关系。方法采用内毒素休克模型。104只大鼠随机分为正常对照组(n=8)、内毒素休克组(n=48)和BH4合成抑制剂2,4二胺6羟基嘧啶(DAHP)拮抗组(n=48)。肝、肺、肾组织BH4含量用反相高效液相色谱法测定,组织三磷酸鸟苷环水解酶I(GTPCHI,BH4合成的首要限速酶)基因表达采用逆转录PCR方法检测。结果内毒素攻击后0.5～2h动物肝、肺、肾组织BH4含量即开始升高(P<0.05),6～12h达峰值(P<0.01),此后逐渐降低;同时,组织GTPCHImRNA表达均明显高于正常对照组(P<0.05)。给予DAHP处理后,2～24h肝、肺、肾组织BH4水平均显著低于内毒素休克组(P<0.05或0.01),肝、肾组织GTPCHImRNA表达各时相点亦明显下调,肺组织12h后降低至正常对照范围。反映肝、肾功能指标和肺组织髓过氧化物酶活性均有不同程度地下降(P<0.05或0.01)。结论生物喋呤参与了内毒素诱发组织损害的病理生理过程,抑制BH4合成有助于减轻脓毒性休克所致过度炎症反应和多器官功能损害。
Objective To investigate the changes of biopterin (BH4) and its relationship with multiple organ damage in endotoxin-shocked animals such as liver, lung and kidney. Methods Endotoxic shock model was used. One hundred and four rats were randomly divided into normal control group (n = 8), endotoxin shock group (n = 48) and BH4 synthetic inhibitor 2,4-diamine 6-hydroxy pyrimidine group (n = 48). The contents of BH4 in liver, lung and kidney were determined by reverse-phase high-performance liquid chromatography (RP-HPLC). The expression of GTPCHI (primary rate-limiting enzyme in BH4 synthesis) was detected by reverse transcription PCR. Results The content of BH4 began to increase in liver, lung and kidney 0.5 ~ 2 h after endotoxin challenge (P <0.05), and peaked at 6 ~ 12 h (P <0.01), and then gradually decreased. At the same time, the expression of GTPCHI mRNA was significantly higher In normal control group (P <0.05). After DAHP treatment, the levels of BH4 in the liver, lung and kidney tissue were significantly lower than those in the endotoxic shock group (P <0.05 or 0.01) at 2 ~ 24 hours, and the GTPCHI mRNA expression in liver and kidney tissues was also significantly down-regulated at each time point. Reduce to the normal control range. Reflect the indicators of liver and kidney and lung tissue myeloperoxidase activity decreased to varying degrees (P <0.05 or 0.01). Conclusion Biopterin is involved in the pathophysiological process of endotoxin-induced tissue damage. Inhibition of BH4 synthesis may help to reduce the excessive inflammatory reaction and multiple organ damage caused by septic shock.