Fornai M, Colucci R, Antonioli L, Ippolito C, Segnani C, Buccianti P, Marioni A, Chiarugi M, Villanacci V, Bassotti G, Blandizzi C, Bernardini N
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Br J Pharmacol. 2014 Aug;171(15):3728-40. doi: 10.1111/bph.12733.
The COX isoforms (COX-1, COX-2) regulate human gut motility, although their role under pathological conditions remains unclear. This study examines the effects of COX inhibitors on excitatory motility in colonic tissue from patients with diverticular disease (DD).
Longitudinal muscle preparations, from patients with DD or uncomplicated cancer (controls), were set up in organ baths and connected to isotonic transducers. Indomethacin (COX-1/COX-2 inhibitor), SC-560 (COX-1 inhibitor) or DFU (COX-2 inhibitor) were assayed on electrically evoked, neurogenic, cholinergic and tachykininergic contractions, or carbachol- and substance P (SP)-induced myogenic contractions. Distribution and expression of COX isoforms in the neuromuscular compartment were assessed by RT-PCR, Western blot and immunohistochemical analysis.
In control preparations, neurogenic cholinergic contractions were enhanced by COX inhibitors, whereas tachykininergic responses were blunted. Carbachol-evoked contractions were increased by indomethacin or SC-560, but not DFU, whereas all inhibitors reduced SP-induced motor responses. In preparations from DD patients, COX inhibitors did not affect electrically evoked cholinergic contractions. Both indomethacin and DFU, but not SC-560, decreased tachykininergic responses. COX inhibitors did not modify carbachol-evoked motor responses, whereas they counteracted SP-induced contractions. COX-1 expression was decreased in myenteric neurons, whereas COX-2 was enhanced in glial cells and smooth muscle.
In control colon, COX-1 and COX-2 down-regulate cholinergic motility, whereas both isoforms enhance tachykininergic motor activity. In the presence of DD, there is a loss of modulation by both COX isoforms on the cholinergic system, whereas COX-2 displays an enhanced facilitatory control on tachykininergic contractile activity.
环氧化酶同工型（COX-1、COX-2）调节人体肠道运动，但其在病理条件下的作用仍不清楚。本研究检测了COX抑制剂对憩室病（DD）患者结肠组织兴奋性运动的影响。
将DD患者或无并发症癌症患者（对照组）的纵行肌标本置于器官浴槽中，并连接到等张换能器上。检测吲哚美辛（COX-1/COX-2抑制剂）、SC-560（COX-1抑制剂）或DFU（COX-2抑制剂）对电诱发、神经源性、胆碱能和速激肽能收缩，或卡巴胆碱和P物质（SP）诱导的肌源性收缩的作用。通过逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹法和免疫组织化学分析评估COX同工型在神经肌肉区室的分布和表达。
在对照标本中，COX抑制剂增强神经源性胆碱能收缩，而速激肽能反应减弱。吲哚美辛或SC-560增加卡巴胆碱诱发的收缩，但DFU无此作用，而所有抑制剂均降低SP诱导的运动反应。在DD患者的标本中，COX抑制剂不影响电诱发的胆碱能收缩。吲哚美辛和DFU均降低速激肽能反应，但SC-560无此作用。COX抑制剂不改变卡巴胆碱诱发的运动反应，但可对抗SP诱导的收缩。肌间神经元中COX-1表达降低，而胶质细胞和平滑肌中COX-2表达增强。
在对照结肠中，COX-1和COX-2下调胆碱能运动，而两种同工型均增强速激肽能运动活性。在DD存在的情况下，两种COX同工型对胆碱能系统的调节作用丧失，而COX-2对速激肽能收缩活性表现出增强的促进性控制作用。
