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本实验从神经源性炎症的角度探讨结肠炎(colitis)发病的机理,并为神经源性结肠炎的假说提供直接的证据。健康雄性Sprague-Dawley大鼠(180～220g)经水合氯醛腹腔麻醉后,将PE-10管插入脊髓蛛网膜下腔达T12～L5水平。鞘内(intrathecal,ith)注射P物质(substance P,SP),每天一次,共14天。神经激肽-1(neurokinin-1,NK1)受体拮抗剂([D-Pro2,D-Trp7,9]-SP,22.4μg)于每次ith注射SP前10min ith预处理。观察疾病活动指数(disease active index,DAI)、结肠和脊髓组织的大体/镜下病理、以及移动抑制因子(migration inhibitory factor,MIF)蛋白的表达。结果显示:ith注射SP 10μg和20μg能够引起大鼠DAI明显升高、结肠组织炎性细胞浸润、腺体萎缩和MIF高表达(与生理盐水组相比,P<0.05,P<0.01);但在脊髓,仅在ith注射SP 20μg组见到轻度充血水肿,并无明显神经元坏死。NK1受体拮抗剂预处理,能够延长ith注射SP 20μg后DAI开始升高的潜伏期、减小DAI升高的幅度、抑制MIF在结肠组织的高表达。上述实验结果表明,ith注射SP能够引起大鼠结肠炎,该效应是通过激活脊髓NK1受体实现的,肠组织的MIF参与了此炎症过程。脊髓高浓度SP能通过NK1受体介导结肠炎这一发现可能具有潜在的临床意义。
This study explored the pathogenesis of colitis from a neurogenic inflammation perspective and provided direct evidence for the hypothesis of neurogenic colitis. Healthy male Sprague-Dawley rats (180-220 g) were anesthetized with chloral hydrate, and inserted into the spinal cord subarachnoid space at T12-L5. Intrathecal injection of substance P (SP) once daily for 14 days. Neurokinin-1 (NK1) receptor antagonist ([D-Pro2, D-Trp7,9] -SP, 22.4 μg) was pretreated with ith 10 min before each ith injection of SP. The disease active index (DAI), gross / microscopic pathology of colon and spinal cord tissue, and the expression of migration inhibitory factor (MIF) protein were observed. The results showed that ith injection of 10 μg and 20 μg of SP could significantly increase the DAI in rats, infiltration of inflammatory cells in the colon tissues, glandular atrophy and high expression of MIF (P <0.05, P <0.01 compared with the saline group) In the spinal cord, mild hyperemia and edema were seen only in the ith injection of 20 μg of ith group, with no apparent neuronal necrosis. NK1 receptor antagonist pretreatment, can be extended ith injection of 20μg of DAI began to increase the incubation period, reducing the amplitude of DAI, inhibiting MIF high expression in the colon tissue. The above experimental results show that ith injection of SP can induce colitis in rats by activating spinal NK1 receptor, and MIF of intestinal tissue is involved in this inflammatory process. The finding that high levels of spinal cord SP can mediate colitis through the NK1 receptor may have potential clinical implications.