Inhibitors of poly (ADP-ribose) polymerase modulate signal transduction pathways in colitis.
Inhibitors of poly (ADP-ribose) polymerase modulate signal transduction pathways in colitis.
复制标题
聚（ADP-核糖）聚合酶抑制剂调节结肠炎中的信号转导途径。
DOI：
10.1016/s0014-2999(03)01726-6
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发表时间：
2003
影响因子：
5
通讯作者：
Hake,PaulW
中科院分区：
文献类型：
--
作者：
Zingarelli,Basilia;O'Connor,Michael;Hake,PaulW
在炎症性肠病期间，氧化和亚硝化应激会诱导 DNA 损伤和核酶聚 (ADP-核糖) 聚合酶 (PARP) 的激活，导致细胞内能量消耗、肠屏障功能障碍和细胞死亡。我们研究的目的是评估体内抑制 PARP 对大鼠实验性结肠炎的治疗效果，这种结肠炎是由直肠滴注三硝基苯磺酸 (TNBS) 引起的。在媒介物处理的大鼠中，TNBS 处理导致结肠糜烂和溃疡。中性粒细胞浸润（由结肠中的髓过氧化物酶活性指示）与硝基酪氨酸的形成和显着的细胞凋亡相关。还发现血浆硝酸盐/亚硝酸盐、一氧化氮 (NO) 代谢物水平升高。这些炎症事件与结肠中核因子-κB (NF-κB) 和激活蛋白-1 (AP-1) 的激活有关。 NF-κB 在第 3 天和第 7 天被激活最大，而 AP-1 在 TNBS 给药后第 1 天增加，此后下降。用 PARP 抑制剂 3-氨基苯甲酰胺或 1,5-二羟基异喹啉治疗大鼠，解决了结肠损伤并降低了血浆 NO 代谢物水平。损伤的消除与中性粒细胞浸润、硝基酪氨酸形成和细胞凋亡的减少有关。 PARP 抑制剂治疗还减少了结肠中 NF-κB 和 AP-1 的 DNA 结合。这些数据证明 PARP 的药理抑制可改善结肠炎。炎症过程的减少与信号转导途径激活的改变有关。
During inflammatory bowel diseases, oxidative and nitrosative stress induces DNA damage and activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), resulting in depletion of intracellular energetics, intestinal barrier dysfunction and cellular death. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in experimental colitis, which was induced by rectal instillation of trinitrobenzene sulfonic acid (TNBS) in rats. In vehicle-treated rats, TNBS treatment resulted in colonic erosion and ulceration. Neutrophil infiltration (indicated by myeloperoxidase activity in the colon) was associated with formation of nitrotyrosine and marked apoptosis. Elevated levels of plasma nitrate/nitrite, metabolites of nitric oxide (NO), were also found. These inflammatory events were associated with the activation of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) in the colon; NF-κB was maximally activated at 3 and 7 days, whereas AP-1 increased 1 day after TNBS administration and declined thereafter. Treatment of the rats with the PARP inhibitors, 3-aminobenzamide or 1,5-dihydroxyisoquinoline, resolved colonic damage and reduced plasma levels of NO metabolites. Resolution of the damage was associated with reduction of neutrophil infiltration, nitrotyrosine formation and apoptosis. Treatment with PARP inhibitors also reduced DNA binding of NF-κB and AP-1 in the colon. These data demonstrate that pharmacological inhibition of PARP ameliorates colitis. Reduction of the inflammatory process is associated with modification of the activation of signal transduction pathways.