Prostaglandin E2, Produced by Mast Cells in Colon Tissues From Patients With Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice
Prostaglandin E2, Produced by Mast Cells in Colon Tissues From Patients With Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice
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DOI：
10.1053/j.gastro.2020.02.022
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发表时间：
2020-06-01
期刊：
影响因子：
29.4
通讯作者：
Owyang, Chung
中科院分区：
文献类型：
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作者：
Grabauskas, Gintautas;Wu, Xiaoyin;Owyang, Chung
背景和目的：内脏超敏反应在肠易激综合征（IBS）患者中很常见。我们研究了炎性分子，如组胺和蛋白酶，是否会激活肾上腺素内过氧化物合酶2（也称为COX 2），以增加肥大细胞合成前列腺素E-2（PGE 2），从而激活背根神经节中的受体PTGER 2（也称为EP 2），以促进内脏高敏感性。方法：我们使用酶联免疫吸附试验测量IBS腹泻患者（IBS-D; 18名女性和5名男性;年龄28-60岁）、健康个体（对照组，n = 24）、小鼠和大鼠结肠粘膜中肥大细胞自发释放分子的水平。我们在结肠内给予结肠活检上清液、组胺、PGE 2、针对EP 2的小干扰RNA或F2 R样胰蛋白酶受体1（F2 RL 1，也称为蛋白酶激活受体2 [PAR 2]）激动剂后，测量了啮齿动物对结直肠扩张的内脏反应。我们研究了由肥大细胞产生的COX 2在内脏高敏感性的介导中的作用，使用Ptgs 2中Y385 F取代的小鼠（Ptgs 2（Y385 F）小鼠），肥大细胞缺陷（W/W-V）小鼠和W/W-V小鼠注射来自野生型或Ptgs 2（Y385 F）小鼠的肥大细胞。研究结果：与对照组相比，IBS-D患者的结肠活检组织中PGE 2、COX 2信使RNA和蛋白质水平升高，这是基于酶联免疫吸附试验。免疫组化显示COX 2主要分布在肥大细胞中。结肠内输注IBS-D活检上清液的大鼠产生3- 4倍增加内脏反应结直肠扩张，这是与PGE 2，组胺和类胰蛋白酶在结肠粘膜中的显着增加。肥大细胞稳定剂、COX 2抑制剂或EP 2敲低可阻止这些增加。结肠内给药IBS-D患者活检组织的上清液不能诱导内脏高敏感性或增加W/W-V和Ptgs 2（Y385 F）小鼠的PGE 2水平。在W/W-V小鼠中重建肥大细胞恢复内脏高敏感性反应。结论：结肠肥大细胞合成PGE 2的异常似乎诱导IBS-D患者内脏高敏感性。
BACKGROUND AND AIMS: Visceral hypersensitivity is common in patients with irritable bowel syndrome (IBS). We investigated whether inflammatory molecules, such as histamine and proteases, activate prostaglandin-endoperoxide synthase 2 (also called COX2) to increase the synthesis of prostaglandin E-2 (PGE2) by mast cells, which activates the receptor PTGER2 (also called EP2) in the dorsal root ganglia to promote visceral hypersensitivity. METHODS: We used an enzyme-linked immunosorbent assay to measure levels of spontaneous release of molecules from mast cells in colonic mucosa from patients with IBS with diarrhea (IBS-D; 18 women and 5 men; aged 28-60 years), healthy individuals (controls, n = 24), mice, and rats. We measured visceromotor responses to colorectal distension in rodents after intracolonic administration of colon biopsy supernatants, histamine, PGE2, a small interfering RNA against EP2, or an agonist of F2R like trypsin receptor 1 (F2RL1, also called protease-activated receptor 2 [PAR2]). We investigated the role of COX2, produced by mast cells, in mediation of visceral hypersensitivity using mice with the Y385F substitution in Ptgs2 (Ptgs2(Y385F) mice), mast cell-deficient (W/W-V) mice, and W/W-V mice given injections of mast cells derived from wild-type or Ptgs2(Y385F) mice. RESULTS: Colon biopsies from patients with IBS-D had increased levels of PGE2, based on enzyme-linked immunosorbent assay, and COX2 messenger RNA and protein, compared with control biopsies. Immunohistochemistry showed that most of the COX2 was in mast cells. Intracolonic infusions of rats with IBS-D biopsy supernatants generated a 3- to 4-fold increase in visceromotor responses to colorectal distension; this was associated with significant increases in PGE2, histamine, and tryptase in the colonic mucosa. These increases were prevented by a mast cell stabilizer, COX2 inhibitor, or knockdown of EP2. Intracolonic administration of supernatants from biopsies of patients with IBS-D failed to induce visceral hypersensitivity or increase the level of PGE2 in W/W-V and Ptgs2(Y385F) mice. Reconstitution of mast cells in W/W-V mice restored the visceral hypersensitivity response. CONCLUSIONS: Abnormal synthesis of PGE2 by colonic mast cells appears to induce visceral hypersensitivity in patients with IBS-D.