Prostaglandin E 2 , Produced by Mast Cells in Colon Tissues From Patients With Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice.

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.
(Copyright © 2020. Published by Elsevier Inc.)