Proteinase-Activated Receptor-2 in the Pathogenesis of Gastroesophageal Reflux Disease

Kandulski, Arne; Wex, Thomas; Mönkemüller, Klaus; Kuester, Doerthe; Fry, Lucía C.; Roessner, Albert; Malfertheiner, Peter

doi:10.1038/ajg.2010.265

Cited by 65 publications

(74 citation statements)

References 31 publications

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“…More obvious PAR-2 reactivity in the basal and suprabasal layers of the esophageal mucosa was detected in GERD patients. In fact, the observation of stronger PAR-2 staining in GERD patients, and superficial epithelial PAR-2 staining in some specimens from normal esophagus, is consistent with previous studies (13,18). However, PAR-2 was mainly located on the basal and suprabasal layers in GERD patients in our study.…”

Section: Discussionsupporting

confidence: 81%

“…However, immunohistochemistry showed much stronger immunoreactivity in the trypsin-treated group in the cytosol. In previous studies, immunohistochemical staining of PAR-2 was always presented as cytosolic staining in esophageal epithelial cells (13,18). PAR-2 undergoes a ␤-arrestin-dependent receptor endocytosis after its activation (3).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, protease-activated receptor-2 (PAR-2) has been verified to participate in IL-8 production in esophageal epithelial cells (36), and PAR-2 gene expression was upregulated in the mucosa of patients with GERD and correlated positively with IL-8 expression (18). PAR-2 is a seven-transmembrane trimer G protein-coupled receptor involved in inflammatory and neuroinflammatory epithelial responses in the gut (29).…”

mentioning

confidence: 99%

“…Most of the data to date have been obtained from immortalized cells in monolayer, which are far different from normal esophagus with respect to intercellular cross talk, polarized cell morphology, and barrier function (18,38). To offer a feasible and more esophageal-like cell model, an air-liquid interface (ALI) system with normal human esophageal epithelial cells (HEEC) has been adopted to simulate esophageal stratified squamous epithelial cell layers in vitro (7,26).…”

mentioning

confidence: 99%

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Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model

Shan

Oshima

Chen

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model

Shan

Oshima

Chen

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Moreover, an induction of proteinase-activated receptor-2 (PAR-2) expression was reported in the esophageal mucosa of GERD patients, which correlated well with mucosal inflammatory changes and elevated tissue interleukin (IL)-8 concentrations, providing a possible mechanism for proinflammatory changes in GERD [10]. Furthermore, PAR-2 also mediates nociception via the release of substance P [11].…”

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confidence: 99%

Visceral Hypersensitivity in Non-erosive Reflux Disease: Neurogenic Overwhelming in Esophagus?

Chen

2013

Dig Dis Sci

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The mechanism underlying the pathogenesis of heartburn and chest pain in gastro-esophageal reflux disease (GERD) has not been clearly established. An important advance in understanding how heartburn is experienced has been accomplished with the reporting of dilated intracellular spaces (DIS) in the esophageal mucosa of patients with erosive GERD and non-erosive reflux disease (NERD) [1]. Although the presence of DIS provides a theoretical pathway for direct entry of hydrogen ions into the mucosa [2], its relationship to esophageal barrier function is still controversial since there are no direct measurements of esophageal acid permeability in vivo to support its contribution to barrier function. Another important breakthrough is the detection of transient receptor potential vanilloid subfamily member-1 receptors (TRPV1) in the esophageal mucosa [3], which may potentially contribute to visceral hypersensitivity as one of the important mechanisms in patients with NERD [4]. This notion is supported by the observation that perception of heartburn and esophageal sensitization can be induced by TRPV1 activation after the exposure to capsaicin and related TRPV1 activators such as heat and acid [5]. TRPV1 activation has also been hypothesized to induce neurogenic inflammation by the release of substance P and calcitonin-gene-related peptide (CGRP) in primary afferent neurons [6]. These neuropeptides mediate nociception and neurogenic inflammation via neurokinin 1 receptor (NK1R) for substance P and receptor activity-modifying protein 1 (RAMP1) for CGRP [7][8][9].Therefore, the upregulation of TRPV1 expression in the esophageal mucosa is likely explanation for the phenomenon of visceral sensitization in NERD. Moreover, an induction of proteinase-activated receptor-2 (PAR-2) expression was reported in the esophageal mucosa of GERD patients, which correlated well with mucosal inflammatory changes and elevated tissue interleukin (IL)-8 concentrations, providing a possible mechanism for proinflammatory changes in GERD [10]. Furthermore, PAR-2 also mediates nociception via the release of substance P [11]. Finally, although anion-sensing ion channels (ASICs) have been implicated in the chemosensitivity in primary afferent fibers [12], its clinical implication is yet unclear in GERD and is thought to be more likely referred to the mechanosensitivity of the esophagus.In this issue of Digestive Diseases and Sciences [13], Yoshida et al. test the hypothesis regarding the role of nociceptors and neuropeptides in the pathogenesis of visceral hypersensitivity of NERD by examining the expression of acid-sensitive nociceptors including TRPV1, ASIC-3, PAR-2, and neuropeptides such as substance P and CGRP with their cognate receptors NK1R and RAMP1 in the esophageal mucosa of NERD patients as compared with age-matched healthy controls. Not surprisingly, increased mRNA expression for TRPV1 and PAR-2 was present in the esophageal mucosa of NERD patients accompanied by a similar increase in substance P protein level and mRNA of its receptor...

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Pathophysiology of Gastroesophageal Reflux Disease and Natural History of Barrett’s Esophagus

Iovino

Santonicola

Trudgill

2018

Revisiting Barrett's Esophagus

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Proteinase-Activated Receptor-2 in the Pathogenesis of Gastroesophageal Reflux Disease

Abstract: This study provides evidence of the functional importance of PAR-2-mediated pathways in the pathogenesis of GERD and GERD-associated mucosal alterations and inflammatory changes.

Cited by 65 publications

References 31 publications

Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model

Trypsin impaired epithelial barrier function and induced IL-8 secretion through basolateral PAR-2: a lesson from a stratified squamous epithelial model

Visceral Hypersensitivity in Non-erosive Reflux Disease: Neurogenic Overwhelming in Esophagus?

Pathophysiology of Gastroesophageal Reflux Disease and Natural History of Barrett’s Esophagus

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