背景:众所周知,肠道炎症会通过对肠神经系统的影响而引起肠道运动障碍。已证明胶质源性神经营养因子(GDNF)具有抗炎作用和神经元保护作用。这项研究的目的是研究GDNF是否可以改善炎症诱导的肠道动力障碍。
方法:在葡聚糖硫酸钠(DSS)诱导的实验性结肠炎中,结肠内施用编码GDNF的重组腺病毒载体(Ad-GDNF)。测量疾病活动指数(DAI)和组织学评分。使用酚红测量结肠运输,并以几何中心进行评估。PGP9.5免疫染色用于检查肠神经元的数量和分布。肿瘤坏死因子-α(TNF-α)的表达,白细胞介素-1β(IL-1β),用ELISA法检测髓过氧化物酶(MPO)活性。Akt的表达,通过蛋白质印迹法分析caspase-3,bcl-2和PGP9.5。
结果:观察到显著的神经元细胞损失和结肠运输的显著延迟,伴随着炎症后的神经元损失。GDNF通过以下方式部分预防肠神经元的损失,并显着改善实验性结肠炎和延迟的结肠运输,至少在某种程度上,下调TNF-α和IL-1β的表达,白细胞浸润减少,和抑制神经元细胞凋亡。
结论:GDNF减轻DSS诱导的结肠炎的炎症并改善结肠运输延迟。GDNF可能是治疗UC患者肠动力障碍的有用治疗剂。
BACKGROUND: Intestinal inflammation is well known to cause gut dysmotility through the effects on the enteric nervous system. Glial-derived neurotrophic factor (GDNF) has been demonstrated to have anti-inflammatory effects and neuronal protective actions. The aim of this study was to investigate whether the GDNF could improve inflammation-induced gut dysmotility.
METHODS: Recombinant adenoviral vectors encoding GDNF (Ad-GDNF) were administered intracolonically in experimental colitis induced by dextran sulfate sodium (DSS). The disease activity index (DAI) and histological score were measured. Colonic transit was measured by using phenol red and assessed with the geometric center. PGP 9.5 immunostaining was used to examine the number and distribution of enteric neurons. The expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and myeloperoxidase (MPO) activity were measured by ELISA assay. The expression of Akt, caspase-3, bcl-2 and PGP 9.5 was analyzed by western blot assay.
RESULTS: A significant neuronal cell loss and a significant delay in colonic transit accompanied with the neuronal loss following inflammation were observed. GDNF prevented partially the loss of enteric neurons and ameliorated significantly experimental colitis and delayed colonic transit by, at least in part, down-regulation of TNF-α and IL-1β expression, decrease of infiltration of leukocytes, and inhibition of neuronal cell apoptosis.
CONCLUSIONS: GDNF reduces inflammation and improves delayed colonic transit in DSS-induced colitis. GDNF may be a useful therapeutic agent for the treatment of gut dysmotility in patients with UC.