Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity
Dextran sulfate sodium-induced colonic histopathology, but not altered epithelial ion transport, is reduced by inhibition of phosphodiesterase activity
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DOI：
10.1016/s0002-9440(10)65087-0
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发表时间：
2000-06-01
影响因子：
6
通讯作者：
McKay, DM
中科院分区：
文献类型：
--
作者：
Diaz-Granados, N;Howe, K;McKay, DM
在关节炎和呼吸道炎症模型中，抑制磷酸二酯酶(PDE)活性是有益的，在这里，我们通过将小鼠暴露在4%(w/v)葡聚糖硫酸钠(DSS)饮用水中5天来评估PDE抑制剂对结肠炎的调节能力，其中包括或不使用PDE 4型抑制剂罗利普兰或非选择性PDE抑制剂己酮可可碱(均为5 mg/kg，每天两次)。对照组只接受生理盐水、赋形剂或药物。检测结肠组织学、髓过氧化物酶(MPO)和肿瘤坏死因子-α(TNF-α)水平，以及上皮离子转运(基础状态和神经电刺激、卡巴胆碱和Forsklin刺激)。DSS治疗的小鼠表现出不同程度的腹泻，中远端结肠的显著组织病理学改变，MPO活性升高，对所有三种促分泌刺激的反应降低(>；50%)。罗利普兰和己酮可可碱治疗显著降低了结肠组织病理学和MPO水平的严重程度。两种PDE抑制剂对DSS诱导的结肠炎引起的离子转运事件的减少都没有任何影响。然而，尽管DSS治疗3天后受刺激的离子转运事件仍然减少，DSS+罗利普兰治疗的小鼠的结肠段的分泌反应性表现出增强的恢复，尤其是对卡巴胆碱的分泌反应。这些发现表明，特异性的PDE4抑制可以显著减少结肠炎引起的组织损伤，促进正常结肠功能的恢复。
Inhibition of phosphodiesterase (PDE) activity is beneficial in models of arthritis and airway inflammation, Here we assessed the ability of PDE inhibitors to modulate colitis by exposing mice to 4% (w/v) dextran sulfate sodium (DSS) drinking water for 5 days with or without rolipram, an Inhibitor of PDE type 4, or the nonselective PDE inhibitor, pentoxifylline (both at 5 mg/kg, i.p., twice daily). Controls received saline, vehicle, or drug only. Colonic histology, myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-alpha) levels, and epithelial ion transport (baseline and stimulated by electrical nerve stimulation, carbachol, and forskolin) were examined. DSS-treated mice displayed a variable diarrhea, significant histopathology in the mid-distal colon, elevated MPO activity, and reduced (> 50%) responses to all three pro-secretory stimuli. Treatment with rolipram, and to a lesser extent pentoxifylline, significantly reduced the severity of the colonic histopathology and MPO levels. Neither PDE inhibitor had any affect on the diminished ion transport events caused by DSS-induced colitis. However, although stimulated ion transport events were still reduced 3 days after DSS treatment, colonic segments from DSS + rolipram-treated mice displayed enhanced recovery in their secretory responsiveness, particularly to carbachol, These findings indicate that specific PDE4 inhibition can significantly reduce the tissue damage that accompanies colitis and enhance recovery of normal colonic function.