Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestine
Insights from a novel model of slow-transit constipation generated by partial outlet obstruction in the murine large intestine
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DOI：
10.1152/ajpgi.00238.2012
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发表时间：
2012-11-01
影响因子：
4.5
通讯作者：
Smith, Terence K.
中科院分区：
文献类型：
--
作者：
Heredia, Dante J.;Grainger, Nathan;Smith, Terence K.
慢传输型便秘(STC)的发病机制尚不清楚。在50%的STC患者中，报告了某种形式的出口梗阻；此外，延长的结肠与STC患者有关。我们的目标是1)建立部分出口梗阻引起的STC小鼠模型，2)确定这是否会导致结肠延长，从而激活抑制的“隐蔽反射”，这可能有助于人类的STC。使用荷包缝合，我们物理上减少了C57BL/6小鼠的最大肛门括约肌开放。4d后，安乐死(急性梗阻)、拆线(松解)或反复拆线更换(慢性梗阻，持续24~31d)。在部分梗阻的小鼠中，我们观察到肌肉和粘膜中环氧合酶(COX)-2的水平增加，大肠延长受阻，运输减慢，非传播性结肠移行运动复合体(CMMCs)，缺乏粘膜反射，由于缺乏自发抑制连接电位而导致去极化的环状肌肉慢波活动，肌肉肥大，以及无粘膜准备中的CMMCs。空肠梗阻的延长产生了明显的隐蔽反射。去除阻塞物或加入COX-2拮抗剂(体外和体内)可恢复膜电位、自发抑制连接电位、CMMC增殖和粘膜反射。我们得出结论，部分出口梗阻增加了COX-2，导致结肠过度兴奋。这种过度兴奋在很大程度上是由于前列腺素只抑制下行抑制神经通路。结肠伸长所激活的隐蔽反射抑制了运动能力的上调。
The mechanisms underlying slow-transit constipation (STC) are unclear. In 50% of patients with STC, some form of outlet obstruction has been reported; also an elongated colon has been linked to patients with STC. Our aims were 1) to develop a murine model of STC induced by partial outlet obstruction and 2) to determine whether this leads to colonic elongation and, consequently, activation of the inhibitory "occult reflex," which may contribute to STC in humans. Using a purse-string suture, we physically reduced the maximal anal sphincter opening in C57BL/6 mice. After 4 days, the mice were euthanized (acutely obstructed), the suture was removed (relieved), or the suture was removed and replaced repeatedly (chronically obstructed, over 24-31 days). In partially obstructed mice, we observed increased cyclooxygenase (COX)-2 levels in muscularis and mucosa, an elongated impacted large bowel, slowed transit, nonpropagating colonic migrating motor complexes (CMMCs), a lack of mucosal reflexes, a depolarized circular muscle with slow-wave activity due to a lack of spontaneous inhibitory junction potentials, muscle hypertrophy, and CMMCs in mucosa-free preparations. Elongation of the empty obstructed colon produced a pronounced occult reflex. Removal of the obstruction or addition of a COX-2 antagonist (in vitro and in vivo) restored membrane potential, spontaneous inhibitory junction potentials, CMMC propagation, and mucosal reflexes. We conclude that partial outlet obstruction increases COX-2 leading to a hyperexcitable colon. This hyperexcitability is largely due to suppression of only descending inhibitory nerve pathways by prostaglandins. The upregulation of motility is suppressed by the occult reflex activated by colonic elongation.