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.

pH值在4-7范围内的弱酸的作用与胃食管反流病（GERD）的症状有关。GERD患者的前列腺素E ₂（PGE ₂）与烧心症状有关；但是，确切的生产机制仍不清楚。在这项研究中，我们发现暴露于弱酸会增加PGE _2的产生，并在pH值为4-5时达到峰值，在人正常食管细胞（Het-1A）中略有增加，而在食管鳞状细胞癌（KYSE-270）中则表现出较强的作用。在大鼠中，弱酸处理增加了PGE ₂从食道粘膜的释放。胆汁酸鹅去氧胆酸（CDCA），Het-1A和KYSE-270中的环氧合酶2（COX-2）表达上调并诱导PGE ₂在KYSE-270细胞中生产。弱酸诱导的PGE _2的产生被胞质磷脂酶A2（cPLA2），ERK和瞬态受体电位阳离子通道亚家族V成员4（TRPV4）（pH敏感离子通道抑制剂）显着抑制。Hangeshashinto是一种有效的COX-2抑制剂，可大大降低KYSE-270中弱酸和CDCA诱导的PGE ₂水平。这些结果表明，弱酸通过食道上皮细胞中的TRPV4 / ERK / cPLA2诱导PGE _2的产生，提示在胃灼热等GERD症状中起作用。对于GERD的治疗，可能需要将pH值限制在5以下的干预措施。