Abstract
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 E2 (PGE2) 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 PGE2 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 PGE2 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 PGE2 production in KYSE-270 cells. Weak acid-induced PGE2 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 PGE2 levels in KYSE-270. These results indicated that weak acids induce PGE2 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.
Highlights
Gastroesophageal reflux disease (GERD) is an inflammatory disease of the upper gastrointestinal tract characterised by heartburn and acid regurgitation
In the human oesophageal squamous cell carcinoma cell line KYSE-270, PGE2 production increased significantly after exposure to pH 4.5 (P = 0.00000014) and Chenodeoxycholic acid (CDCA) (CDCA [200 μmol/L]; P = 0.0090, CDCA [400 μmol/L]; P = 0.00000025) (Fig. 1b). PGE2 production increased with acidification as pH gradually decreased from 4.7 to pH 4.4 (Fig. 1c)
We demonstrated for the first time that P GE2 production increases in oesophageal epithelial cells in response to a narrow pH range of pH 4–5 via TRPV4/ERK/cytosolic phospholipase A2 (cPLA2) (Fig. 8)
Summary
Gastroesophageal reflux disease (GERD) is an inflammatory disease of the upper gastrointestinal tract characterised by heartburn and acid regurgitation. Despite recent evidence for the role of weak acid reflux, the degree of risk and mechanisms by which it leads to GERD-related symptoms remain unclear. Bile induces P GE2 production in oesophageal epithelial cells by enhancing COX-2 e xpression[16,17,18], few studies have examined the mechanisms of acid-stimulated P GE2 production. We used several types of oesophageal epithelial cells and an animal model to investigate extracellular pH-dependent P GE2 production and the underlying mechanisms, with a focus on weak acids in comparison with bile acid stimulation. We examined the effect of a Kampo medicine, hangeshashinto (HST), which reportedly alleviates reflux-related symptoms in patients with PPI-refractory G ERD19, on PGE2 production
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