Sa1725 H. pylori Infection Directly Induces Methylation Silencing of a Gastric Epithelial Mechano-Sensor, Transient Receptor Potential Vanilloid 4 in Gastric Epithelial Cells

Esophageal visceral hypersensitivity has been proposed to be the pathogenesis of heartburn sensation in nonerosive reflux disease. Protease-activated receptor-2 (PAR-2) is expressed in human esophageal epithelial cells and is believed to play a role in inflammation and sensation. PAR-2 activation may modulate these responses through adenosine triphosphate (ATP) release, which is involved in transduction of sensation and pain. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) are both acid-sensitive nociceptors. However, the interaction among these molecules and the mechanisms of heartburn sensation are still not clear. We therefore examined whether ATP release in human esophageal epithelial cells in response to acid is modulated by TRPV1 and ASICs and whether PAR-2 activation influences the sensitivity of TRPV1 and ASICs. Weak acid (pH 5) stimulated the release of ATP from primary human esophageal epithelial cells (HEECs). This effect was significantly reduced after pretreatment with 5-iodoresiniferatoxin (IRTX), a TRPV1-specific antagonist, or with amiloride, a nonselective ASIC blocker. TRPV1 and ASIC3 small interfering RNA (siRNA) transfection also decreased weak acid-induced ATP release. Pretreatment of HEECs with trypsin, tryptase, or a PAR-2 agonist enhanced weak acid-induced ATP release. Trypsin treatment led to the phosphorylation of TRPV1. Acid-induced ATP release enhancement by trypsin was partially blocked by IRTX, amiloride, or a PAR-2 antagonist. Conversely, acid-induced ATP release was augmented by PAR-2 activation through TRPV1 and ASICs. These findings suggested that the pathophysiology of heartburn sensation or esophageal hypersensitivity may be associated with the activation of PAR-2, TRPV1, and ASICs.

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Heartburn Sensation in Non-Erosive Reflux Disease: Pattern of Superficial Sensory Nerves Expressing TRPV1 and Epithelial Cells Expressing ASIC3 Receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00013.2021 ◽

2021 ◽

Author(s):

Ahsen Ustaoglu ◽

Akinari Sawada ◽

Chung Lee ◽

Wei-Yi Lei ◽

Chien-Lin Chen ◽

...

Keyword(s):

Epithelial Cells ◽

Reflux Disease ◽

Transient Receptor Potential ◽

Sensory Nerve ◽

Receptor Potential ◽

Sensory Nerves ◽

Transient Receptor Potential Vanilloid ◽

Esophageal Mucosa ◽

Transient Receptor Potential Melastatin ◽

Transient Receptor

The underlying causes of heartburn, characteristic symptom of gastro-esophageal reflux disease(GERD), remain incompletely understood. Superficial afferent innervation of the esophageal mucosa in nonerosive reflux disease(NERD) may drive nociceptive reflux perception, but its acid-sensing role has not yet been established. Transient receptor potential vanilloid subfamily member-1(TRPV1), transient receptor potential Melastatin 8(TRPM8), and acid sensing ion channel 3(ASIC3) are regulators of sensory nerve activity and could be important reflux-sensing receptors within the esophageal mucosa. We characterised TRPV1, TRPM8, and ASIC3 expression in esophageal mucosa of GERD patients. We studied 10 NERD, 10 erosive reflux disease(ERD), 7 functional heartburn(FH), and 8 Barrett's esophagus(BE) patients. Biopsies obtained from the distal esophageal mucosa were co-stained with TRPV1, TRPM8, or ASIC3, and CGRP, CD45, or E-cadherin. RNA expression of TRPV1, TRPM8, and ASIC3 was assessed using qPCR. NERD patients had significantly increased expression of TRPV1 on superficial sensory nerves compared to ERD (p=0.028) or BE (p=0.017). Deep intrapapillary nerve endings did not express TRPV1 in all phenotypes studied. ASIC3 was exclusively expressed on epithelial cells most significantly in NERD and ERD patients (p=<0.0001). TRPM8 was expressed on submucosal CD45+ leukocytes. Superficial localisation of TRPV1-immunoreactive nerves in NERD, and increased ASIC3 co-expression on epithelial cells in NERD and ERD suggests a mechanism for heartburn sensation. Esophageal epithelial cells may play a sensory role in acid reflux perception and act interdependently with TRPV1-expressing mucosal nerves to augment hypersensitivity in NERD patients, raising the enticing possibility of topical antagonists for these ion channels as a therapeutic option.

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