Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.
Inhibiting Inducible Nitric Oxide Synthase in Enteric Glia Restores Electrogenic Ion Transport in Mice With Colitis.
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DOI：
10.1053/j.gastro.2015.04.007
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发表时间：
2015-08
期刊：
影响因子：
29.4
通讯作者：
Sharkey KA
中科院分区：
文献类型：
--
作者：
MacEachern SJ;Patel BA;Keenan CM;Dicay M;Chapman K;McCafferty DM;Savidge TC;Beck PL;MacNaughton WK;Sharkey KA
结肠炎患者离子转运控制障碍导致上皮屏障功能障碍。肠神经胶质细胞调节肠屏障功能和结肠离子转运。然而，肠神经胶质细胞是否参与了上皮细胞的低反应性尚不清楚。我们研究了三硝基苯磺酸或葡聚糖硫酸钠诱导的结肠炎小鼠和Il 10 −/−小鼠的肠神经胶质细胞对离子转运的调节。在Ussing室中，在患有或不患有结肠炎的CD 1和Il 10 −/−小鼠的结肠全层段中测量电诱发离子转运。一氧化氮（NO）的生产进行了评估，使用安培法。在小鼠的肝、脾和血液中研究细菌移位。电刺激结肠诱发河豚毒素敏感的氯化物分泌。在患有结肠炎的小鼠中，离子转运几乎完全消失。抑制诱导型一氧化氮合酶（NOS 2），而不是神经元型一氧化氮合酶（NOS 1），部分恢复了诱发的分泌反应。用氟乙酸盐（不是NOS 2抑制剂）阻断神经胶质功能也部分恢复了离子转运。组合的NOS 2抑制和氟乙酸盐施用完全恢复分泌。结肠炎小鼠肠神经胶质功能被阻断后，上皮细胞对血管活性肠肽的反应性增加。在没有结肠炎的小鼠结肠中，NO几乎完全通过NOS 1在肌间神经丛中产生。与没有结肠炎的小鼠相比，结肠炎小鼠的NO产生增加;氟乙酸盐给药阻断了相当大比例的NOS 2。在体内抑制肠神经胶质功能可以降低三硝基苯磺酸诱导的结肠炎和相关细菌移位的严重程度。肠神经胶质细胞中NOS 2的产生增加有助于结肠炎小鼠肠道离子转运的失调。阻断这些小鼠的肠神经胶质功能可恢复上皮屏障功能并减少细菌移位。
Disturbances in the control of ion transport lead to epithelial barrier dysfunction in patients with colitis. Enteric glia regulate intestinal barrier function and colonic ion transport. However, it is not clear whether enteric glia are involved in the epithelial hypo-responsiveness. We investigated enteric glial regulation of ion transport in mice with trinitrobenzene sulphonic acid- or dextran sodium sulfate-induced colitis and in Il10−/− mice. Electrically-evoked ion transport was measured in full-thickness segments of colon from CD1 and Il10−/− mice with or without colitis in Ussing chambers. Nitric oxide (NO) production was assessed using amperometry. Bacterial translocation was investigated in the liver, spleen and blood of mice. Electrical stimulation of the colon evoked a tetrodotoxin-sensitive chloride secretion. In mice with colitis, ion transport almost completely disappeared. Inhibiting inducible NO synthase (NOS2), but not neuronal NOS (NOS1), partially restored the evoked secretory response. Blocking glial function with fluoroacetate, which is not a NOS2 inhibitor, also partially restored ion transport. Combined NOS2 inhibition and fluoroacetate administration fully restored secretion. Epithelial responsiveness to vasoactive intestinal peptide was increased after enteric glial function was blocked in mice with colitis. In colons of mice without colitis, NO was produced in the myenteric plexus almost completely via NOS1. NO production was increased in mice with colitis, compared to mice without colitis; a substantial proportion of NOS2 was blocked by fluoroacetate administration. Inhibition of enteric glial function in vivo reduced the severity of trinitrobenzene sulphonic acid -induced colitis and associated bacterial translocation. Increased production of NOS2 in enteric glia contributes to the dysregulation of intestinal ion transport in mice with colitis. Blocking enteric glial function in these mice restores epithelial barrier function and reduces bacterial translocation.