Weak acids induce PGE(2) production in human oesophageal cells: novel mechanisms underlying GERD symptoms

The role of weak acids with pH values in the range of 4–7 has been implicated in the symptoms of gastroesophageal reflux disease (GERD). Prostaglandin E(2) (PGE(2)) is associated with heartburn symptom in GERD patients; however, the precise productive mechanisms remain unclear. In this study, we revealed that exposure to weak acids increases PGE(2) production with a peak at pH 4–5, slightly in human normal oesophageal cells (Het-1A), and robustly in oesophageal squamous carcinoma cells (KYSE-270). Release of PGE(2) from the oesophageal mucosa was augmented by weak acid treatment in rat. Chenodeoxycholic acid (CDCA), a bile acid, upregulated cyclooxygenase-2 (COX-2) expression in Het-1A and KYSE-270 and induced PGE(2) production in KYSE-270 cells. Weak acid-induced PGE(2) production was significantly inhibited by cytosolic phospholipase A2 (cPLA2), ERK, and transient receptor potential cation channel subfamily V member 4 (TRPV4), a pH-sensing ion channel, inhibitors. Hangeshashinto, a potent inhibitor of COX-2, strongly decreased weak acid- and CDCA-induced PGE(2) levels in KYSE-270. These results indicated that weak acids induce PGE(2) production via TRPV4/ERK/cPLA2 in oesophageal epithelial cells, suggesting a role in GERD symptoms like heartburn. Interventions targeting pH values up to 5 may be necessary for the treatment of GERD.