Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, PO Box 616,6200 MD Maastricht, The Netherlands.
Eur J Pharmacol. 2010 Mar 10;629(1-3):132-9. doi: 10.1016/j.ejphar.2009.11.064. Epub 2009 Dec 4.
The nuclear enzyme poly(ADP-ribose) polymerse-1 (PARP-1) has previously been reported to play an important role in lipopolysaccharide (LPS)-induced pulmonary inflammation and is highly activated in COPD patients. In the present study, the anti-inflammatory efficacy of a previously identified poly(ADP-ribose) polymerase-1 (PARP-1) inhibiting caffeine metabolite, 1,7-dimethylxanthine, was both in vivo as well as ex vivo evaluated. Orally administered 1,7-dimethylxanthine significantly attenuated lung myeloperoxidase-levels, transcription of IL-6, TNF-alpha, MIP1alpha and MIP2 genes as well as PAR-polymer formation in a mouse model of intratracheally LPS-induced acute pulmonary inflammation. Serum amyloid P component and plasma IL-6 were also lowered in 1,7-dimethylxanthine treated mice, indicating a reduced systemic inflammatory response. In addition, at 24h after LPS administration anti-inflammatory effects of 1,7-dimethylxanthine appeared more pronounced than those of the orally administered PARP-1 inhibitor 3-aminobenzamide. In the second model, in blood of COPD-patients and healthy controls ex vivo pre-incubated with a physiological concentration of 1,7-dimethylxanthine (10microM), LPS-induced production of the cytokines IL-6 and TNF-alpha was significantly suppressed. 1,7-Dimethylxanthine exerts anti-inflammatory effects, both in vivo mouse as well as ex vivo human. These results suggest that the PARP-1 inhibiting caffeine metabolite 1,7-dimethylxanthine may have therapeutic potential in pulmonary inflammatory diseases such as COPD.
核酶多聚（ADP-核糖）聚合酶-1（PARP-1）先前被报道在脂多糖（LPS）诱导的肺炎症中发挥重要作用，并且在 COPD 患者中高度激活。在本研究中，先前鉴定的多聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂咖啡因代谢物 1,7-二甲基黄嘌呤的抗炎功效进行了体内和体外评估。口服给予 1,7-二甲基黄嘌呤可显著减弱 LPS 诱导的急性肺炎症小鼠模型中的肺髓过氧化物酶水平、IL-6、TNF-α、MIP1alpha 和 MIP2 基因的转录以及 PAR 聚合形成。1,7-二甲基黄嘌呤处理的小鼠血清淀粉样蛋白 P 成分和血浆 IL-6 也降低，表明全身炎症反应减轻。此外，在 LPS 给药后 24 小时，1,7-二甲基黄嘌呤的抗炎作用比口服给予的 PARP-1 抑制剂 3-氨基苯甲酰胺更为明显。在第二个模型中，在 COPD 患者和健康对照者的血液中，用生理浓度的 1,7-二甲基黄嘌呤（10μM）体外预孵育后，LPS 诱导的细胞因子 IL-6 和 TNF-α 的产生显著受到抑制。1,7-二甲基黄嘌呤在体内（小鼠）和体外（人）均发挥抗炎作用。这些结果表明，PARP-1 抑制剂咖啡因代谢物 1,7-二甲基黄嘌呤在 COPD 等肺部炎症性疾病中可能具有治疗潜力。
