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 E₂ (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.

中文翻译：

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肠易激综合症患者结肠组织中肥大细胞产生的前列腺素E2有助于小鼠内脏超敏反应。

背景和目标

肠易激综合征在肠易激综合征（IBS）患者中很常见。我们调查了炎症分子（例如组胺和蛋白酶）是否激活了前列腺素-过氧化物合酶2（也称为COX2）以增加肥大细胞对前列腺素E ₂（PGE2）的合成，从而激活了前列腺素-过氧化物合酶2 （也称为EP2）。背根神经节促进内脏超敏反应。

方法

我们使用了一种酶联免疫吸附试验来测定腹泻IBS患者（IBS-D； 18名妇女和5名男性；年龄28-60岁），健康个体（对照组）结肠黏膜肥大细胞中分子自发释放的水平。 ，n = 24），小鼠和大鼠。在结肠内给药结肠活检上清液，组胺，PGE2，针对EP2的小干扰RNA或F2R激动剂（如胰蛋白酶受体1（F2RL1，也称为蛋白酶激活受体2 [PAR2]）后，我们测量了啮齿类动物对结肠扩张的内脏运动反应）。我们使用小鼠在Y385F取代调查COX2的作用，由肥大细胞产生，在内脏超敏反应中介PTGS2（PTGS 2 ^Y385F只小鼠），肥大细胞缺陷（W / W ^V）小鼠和W / W ^V小鼠注射了来自野生型或Ptgs 2 ^Y385F小鼠的肥大细胞。

结果

与对照活检相比，基于酶联免疫吸附测定的IBS-D患者结肠活检具有较高的PGE2水平，以及COX2信使RNA和蛋白质。免疫组织化学显示，大多数COX2位于肥大细胞中。用IBS-D活检上清液对大鼠进行结肠结肠灌注可以使对结肠扩张的内脏运动反应增加3到4倍。这与结肠粘膜中PGE2，组胺和类胰蛋白酶的显着增加有关。肥大细胞稳定剂，COX2抑制剂或EP2的抑制可防止这些增加。结肠内注射IBS-D患者活检的上清液未能引起内脏超敏反应或增加W / W ^V和Ptgs2中的PGE2水平^Y385F 小鼠。W / W ^V小鼠中肥大细胞的重建恢复了内脏超敏反应。

结论

结肠肥大细胞异常合成PGE2似乎会诱发IBS-D患者的内脏超敏反应。