Tissue resistance in the normal and diseased esophagus

Bellizzi, Andrew M.; Nardone, Gerardo; Compare, Debora; Bor, Serhat; Capanoglu, Doga; Farré, Ricard; Neumann, Helmut; Neurath, Markus F.; Chen, Hao; Chen, Xiaoxin

doi:10.1111/nyas.12248

Cited by 5 publications

(5 citation statements)

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“…The nonkeratinized stratified squamous epithelium of the healthy esophagus normally presents an electrically tight barrier against refluxed materials 7 . In the minority of GERD cases classified as erosive reflux disease (ERD), the mucosal barrier is macroscopically breached at the site of erosions, permitting refluxate constituents to reach and activate underlying nociceptive receptors resulting in the symptom of heartburn 8 .…”

Section: Introductionmentioning

confidence: 99%

“…2,6 The nonkeratinized stratified squamous epithelium of the healthy esophagus normally presents an electrically tight barrier against refluxed materials. 7 In the minority of GERD cases classified as erosive reflux disease (ERD), the mucosal barrier is macroscopically breached at the site of erosions, permitting refluxate constituents to reach and activate underlying nociceptive receptors resulting in the symptom of heartburn. 8 Greater than 60% of GERD patients are endoscopically negative (classified as non-erosive reflux disease [NERD]), 9 but on histologic analysis exhibit a widening between cells known as dilated intercellular spaces (DIS).…”

Section: Introductionmentioning

confidence: 99%

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Alginates for Protection Against Pepsin‐Acid Induced Aerodigestive Epithelial Barrier Disruption

et al. 2022

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Objective Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are chronic conditions caused by backflow of gastric and duodenal contents into the esophagus and proximal aerodigestive tract, respectively. Mucosal barrier dysfunction resultant from the synergistic actions of chemical injury and the mucosal inflammatory response during reflux contributes to symptom perception. Alginates effectively treat symptoms of mild to moderate GERD and have recently shown benefit for LPR. In addition to forming a “raft” over gastric contents to reduce acidic reflux episodes, alginates have been found to bind the esophageal mucosa thereby preserving functional barrier integrity measured by transepithelial electrical resistance. The aim of this study was to further examine the topical protective capacity of alginate‐based Gaviscon Advance (GA) and Double Action (GDA) against pepsin‐acid mediated aerodigestive epithelial barrier dysfunction in vitro. Study Design Translational. Methods Immortalized human esophageal and vocal cord epithelial cells cultured in transwells were pretreated with liquid formula GA, GDA, matched viscous placebo solution, or saline (control), then treated for 1 h with saline, acid (pH 3–6) or pepsin (0.1–1 mg/ml) at pH 3–6. Endpoint measure was taken of horseradish peroxidase (HRP) allowed to diffuse across monolayers for 2 h. Results Pepsin (0.1‐1 mg/ml) at pH 3‐6 increased HRP flux through cultures pretreated with saline or placebo (p < 0.05); acid alone did not. GA and GDA prevented barrier dysfunction. Conclusions GA and GDA preserved epithelial barrier function during pepsin‐acid insult better than placebo suggesting that protection was due to alginate. These data support topical protection as a therapeutic approach to GERD and LPR. Laryngoscope, 132:2327–2334, 2022

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alginates for Protection Against Pepsin‐Acid Induced Aerodigestive Epithelial Barrier Disruption

et al. 2022

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“…The permeation of noxious components of the refluxate into the mucosa is normally prevented by a tight barrier formed by the nonkeratinized stratified squamous epithelium (4,18). In patients with esophagitis, the natural mucosal barrier is clearly breached at the site of erosions, and noxious stimuli can easily traverse the mucosa and subsequently activate the underlying nociceptors.…”

mentioning

confidence: 99%

Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis

Weijenborg

Smout

Verseijden³

et al. 2014

American Journal of Physiology-Gastrointestinal and Liver Physi

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Increased esophageal sensitivity and impaired mucosal integrity have both been described in patients with gastroesophageal reflux disease, but the relationship between hypersensitivity and mucosal integrity is unclear. The aim of the present study was to investigate acid sensitivity in patients with erosive and nonerosive reflux disease and control subjects to determine the relation with functional esophageal mucosal integrity changes as well as to investigate cellular mechanisms of impaired mucosal integrity in these patients. In this prospective experimental study, 12 patients with nonerosive reflux disease, 12 patients with esophagitis grade A or B, and 11 healthy control subjects underwent an acid perfusion test and upper endoscopy. Mucosal integrity was measured during endoscopy by electrical tissue impedance spectroscopy and biopsy specimens were analyzed in Ussing chambers for transepithelial electrical resistance, transepithelial permeability and gene expression of tight junction proteins and filaggrin. Patients with nonerosive reflux disease and esophagitis were more sensitive to acid perfusion compared with control subjects, having a shorter time to perception of heartburn and higher perceived intensity of heartburn. In reflux patients, enhanced acid sensitivity was associated with impairment of in vivo and vitro esophageal mucosal integrity. Mucosal integrity was significantly impaired in patients with esophagitis, displaying higher transepithelial permeability and lower extracellular impedance. Although no significant differences in the expression of tight junction proteins were found in biopsies among patient groups, mucosal integrity parameters in reflux patients correlated negatively with the expression of filaggrin. In conclusion, sensitivity to acid is enhanced in patients with gastroesophageal reflux disease, irrespective of the presence of erosions, and is associated with impaired esophageal mucosal integrity. Mucosal integrity of the esophagus is associated with the expression of filaggrin.

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“…TATA box binding protein or GAPDH genes were used as the internal control. The RT 2 Profiler PCR Array Mouse Cytokines and Chemokines (Qiagen) was used to examine Il23a expression in mouse esophageal mucosa.…”

Section: Methodsmentioning

confidence: 99%

“… 1 Most esophageal diseases arise in the context of inflammation and injury. 2 , 3 , 4 For example, esophageal squamous cell cancer (ESCC) accounts for more than 90% of esophageal cancer and develops progressively from inflammation, hyperplasia, dysplasia, carcinoma in situ, to invasive carcinoma. 5 , 6 Epithelial cells are the first line of defense for the esophagus, which is constantly challenged by exposure to irritants (alcohol, tobacco, food antigens, and gastric acid reflux).…”

mentioning

confidence: 99%

IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the Esophagus

Wiles

Alioto

Hodge

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims The epithelial barrier is the host’s first line of defense against damage to the underlying tissue. Upon injury, the epithelium plays a critical role in inflammation. The IκB kinase β (IKKβ)/nuclear factor-κB pathway was shown to be active in the esophageal epithelium of patients with esophageal disease. However, the complex mechanisms by which IKKβ signaling regulates esophageal disease pathogenesis remain unknown. Our prior work has shown that expression of a constitutively active form of IKKβ specifically in esophageal epithelia of mice ( Ikkβca Esophageal Epithelial Cell-Knockin ( EEC-KI ) ) is sufficient to cause esophagitis. Methods We generated ED-L2/Cre;Rosa26-Ikkβca +/L ;Stat3 L/L ( Ikkβca EEC-KI ;Stat3 Esophageal Epithelial Cell Knockout ( EEC-KO ) ) mice, in which the ED-L2 promoter activates Cre recombinase in the esophageal epithelium, leading to constitutive activation of IKKβ and loss of Stat3. Esophageal epithelial tissues were collected and analyzed by immunostaining, RNA sequencing, quantitative real-time polymerase chain reaction assays, flow cytometry, and Western blot. Ikkβca EEC-KI mice were treated with neutralizing antibodies against interleukin (IL)23p19 and IL12p40. Results Here, we report that Ikkβca EEC-KI mice have increased activation of epithelial Janus kinase 2/STAT3 signaling. Stat3 deletion in Ikkβca EEC-KI mice attenuated the neutrophil infiltration observed in Ikkβca EEC-KI mice and resulted in decreased expression of genes related to immune cell recruitment and activity. Blocking experiments in Ikkβca EEC-KI mice showed that STAT3 activation and subsequent neutrophil recruitment are dependent on IL23 secretion. Conclusions Our study establishes a novel interplay between IKKβ and STAT3 signaling in epithelial cells of the esophagus, where IKKβ/IL23/STAT3 signaling controls neutrophil recruitment during the onset of inflammation. GEO accession number: GSE154129.

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Tissue resistance in the normal and diseased esophagus

Cited by 5 publications

References 54 publications

Alginates for Protection Against Pepsin‐Acid Induced Aerodigestive Epithelial Barrier Disruption

Alginates for Protection Against Pepsin‐Acid Induced Aerodigestive Epithelial Barrier Disruption

Hypersensitivity to acid is associated with impaired esophageal mucosal integrity in patients with gastroesophageal reflux disease with and without esophagitis

IκB Kinase-β Regulates Neutrophil Recruitment Through Activation of STAT3 Signaling in the Esophagus

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