Evaldsson C, Rydén I, Rosén A, Uppugunduri S
Division of Clinical Chemistry, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Clin Exp Immunol. 2009 Feb;155(2):330-8. doi: 10.1111/j.1365-2249.2008.03795.x. Epub 2008 Dec 1.
Recent reports demonstrate a role for nucleotides as inflammatory modulators. Uridine, for example, reduces oedema formation and leucocyte infiltration in a Sephadex-induced lung inflammation model. Tumour necrosis factor (TNF) concentration was also reduced. Previous in vivo observations indicated that 4-thiouridine might have similar effects on leucocyte infiltration and TNF release. The aim of this study was thus to investigate the effects of 4-thiouridine in greater detail. We used a Sephadex-induced acute lung inflammation model in Sprague-Dawley rats. The dextran beads were instilled intratracheally into the lungs, which were excised and examined after 24 h. Sephadex alone led to massive oedema formation and infiltration of macrophages, neutrophils and eosinophils. Microgranulomas with giant cell formations were clearly visible around the partially degraded beads. A significant increase in bronchoalveolar lavage fluid (BALF) content of TNF and leukotrienes was also seen. 4-Thiouridine co-administration affected all variables investigated in this model, i.e. oedema, microscopic and macroscopic appearance of lung tissue, total leucocyte and differential leucocyte counts in BALF, TNF and leukotrienes C(4) (LTC(4)), LTD(4 )and LTE(4) in BALF, indicating a reproducible anti-inflammatory effect. In conclusion, we have demonstrated that 4-thiouridine has anti-inflammatory effects similar to those of uridine. To our knowledge, this is the first demonstration of pharmacological 4-thiouridine effects in vivo. The results suggest nucleoside/nucleotide involvement in inflammatory processes, warranting further studies on nucleoside analogues as attractive new alternatives in the treatment of inflammatory diseases.
最近的报告表明核苷酸可作为炎症调节剂发挥作用。例如，尿苷可减少葡聚糖诱导的肺部炎症模型中的水肿形成和白细胞浸润。肿瘤坏死因子（TNF）浓度也有所降低。先前的体内观察表明，4-硫尿苷可能对白细胞浸润和TNF释放有类似作用。因此，本研究的目的是更详细地研究4-硫尿苷的作用。我们在Sprague-Dawley大鼠中使用了葡聚糖诱导的急性肺部炎症模型。将葡聚糖珠经气管内注入肺中，24小时后切除肺并进行检查。单独使用葡聚糖会导致大量水肿形成以及巨噬细胞、中性粒细胞和嗜酸性粒细胞浸润。在部分降解的珠子周围可见带有巨细胞形成的微肉芽肿。支气管肺泡灌洗液（BALF）中TNF和白三烯的含量也显著增加。联合给予4-硫尿苷影响了该模型中研究的所有变量，即水肿、肺组织的微观和宏观外观、BALF中的白细胞总数和分类白细胞计数、BALF中的TNF和白三烯C4（LTC4）、LTD4和LTE4，表明其具有可重复的抗炎作用。总之，我们已证明4-硫尿苷具有与尿苷类似的抗炎作用。据我们所知，这是首次在体内证明4-硫尿苷的药理作用。结果表明核苷/核苷酸参与炎症过程，这使得有必要进一步研究核苷类似物作为治疗炎症性疾病有吸引力的新选择。
