Gastroesophageal Reflux Might Cause Esophagitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid Injury

Souza, Rhonda F.; Huo, Xiaofang; Mittal, Vivek; Schuler, Christopher M.; Carmack, Susanne W.; Zhang, Hui Ying; Zhang, Xi; Yu, Chunhua; Hormi–Carver, Kathy; Genta, Robert M.; Spechler, Stuart J.

doi:10.1053/j.gastro.2009.07.055

Cited by 350 publications

(370 citation statements)

References 35 publications

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“…Recent data suggest that immunemediated mechanisms play a prominent role in the development of GERD and that IL-8 is one of the central cytokines (2,3). Indeed, in our model of subchronic GERD, the rat analogs to human IL-8 (the murine CINC1, -2 and -3) were elevated, supporting an IL-8 involvement in GERD.…”

Section: Discussionmentioning

confidence: 52%

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

Abdel-Aziz

Schneider

Neuhuber

et al. 2015

Mol Med

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Gastro-esophageal reflux disease (GERD) is one of the most common disorders in gastroenterology. Patients present with or without increased acid exposure indicating a nonuniform etiology. Thus, the common treatment with proton pump inhibitors (PPIs) fails to control symptoms in up to 40% of patients. To further elucidate the pathophysiology of the condition and explore new treatment targets, transcriptomics, proteomics and histological methods were applied to a surgically induced subchronic reflux esophagitis model in Wistar rats after treatment with either omeprazole (PPI) or STW5, a herbal preparation shown to ameliorate esophagitis without affecting refluxate pH. The normal human esophageal squamous cell line HET-1A and human endoscopic biopsies were used to confirm our findings to the G-protein-coupled receptor (GPR) 84 in human tissue. Both treatments reduced reflux-induced macroscopic and microscopic lesions of the esophagi as well as known proinflammatory cytokines. Proteomic and transcriptomic analyses identified CINC1-3, MIP-1/3α, MIG, RANTES and interleukin (IL)-1β as prominent mediators in GERD. Most regulated cyto-/chemokines are linked to the TREM-1 signaling pathway. The fatty acid receptor GPR84 was upregulated in esophagitis but significantly decreased in treated groups, a finding supported by Western blot and immunohistochemistry in both rat tissue and HET-1A cells. GPR84 was also found to be significantly upregulated in patients with grade B reflux esophagitis. The expression of GPR84 in esophageal tissue and its potential involvement in GERD are reported for the first time. IL-8 (CINC1-3) and the TREM-1 signaling pathway are proposed, besides GPR84, to play an important role in the pathogenesis of GERD.

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Section: Discussionmentioning

confidence: 52%

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

Abdel-Aziz

Schneider

Neuhuber

et al. 2015

Mol Med

View full text Add to dashboard Cite

show abstract

“…But such an injury should begin at the surface and develop immediately, and there is no evidence of any such direct response. Animal studies regarding reflux esophagitis induced by esophagoduodenostomy reveal that the earliest sign of esophageal inflammation is an infiltration of the submucosa by white cells that is cytokine-mediated and precedes the development of surface lesions by weeks [7]. This immune system response is supported by transmission electron microscopy, which showed no evidence of inflammation in the esophageal mucosa in response to acute stress, hydrochloric acid, ethanol, aspirin or prednisolone [8].…”

supporting

confidence: 51%

Could proton pump inhibitors cause cancer?

Rösch

2014

Expert Review of Clinical Pharmacology

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“…17,19 Kanazawa et al 20 found that contact with refluxate could cause the elevation of IL-8 in the mucosa of NERD patients. IL-8 promoted the aggregation of neutrophils and the active substance from neutrophils could cause mucosa injury.…”

Section: Discussionmentioning

confidence: 99%

Esophageal Baseline Impedance Reflects Mucosal Integrity and Predicts Symptomatic Outcome With Proton Pump Inhibitor Treatment

Xie

Sifrim

et al. 2018

J Neurogastroenterol Motil

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Background/AimsEsophageal baseline impedance, which is decreased in gastroesophageal reflux disease (GERD) patients, is related to the severity of acid reflux and the integrity of the esophageal mucosa. The study aims to compare the baseline impedance and the dilated intercellular spaces (DIS) within patients with typical reflux symptoms and to evaluate the correlation of baseline impedance with DIS, esophageal acid exposure, as well as the efficacy of proton pump inhibitor (PPI) treatment. MethodsNinety-two patients and 10 healthy controls were included in the study. Erosive esophagitis (EE) was defined by esophageal mucosal erosion under upper endoscopy. Patients without mucosa erosion were divided into groups with pathologic acid reflux (nonerosive reflux disease [NERD]) or with hypersensitive esophagus. The biopsies of esophageal mucosa were taken 2-4 cm above the gastroesophageal junction Z-line during upper endoscopy for DIS measurement. All the patients received esomeprazole 20 mg twicedaily treatment for 8 weeks. The efficacy of esomeprazole was evaluated among all patients. ResultsThe intercellular spaces were dilated in both EE and NERD patients (P < 0.05). The value 0.73 mm could be used as the cut-off DIS value to distinguish patients from controls (area under the curve [AUC] = 0.849, P < 0.01). One thousand seven hundred sixty-four ohms could be used as the cut-off impedance values to distinguish patients from controls (AUC = 0.794, P < 0.01). The baseline impedance was decreased in both EE patients and NERD patients, and negatively correlated to the acid exposure time (r = -0.527, P < 0.05). There was a weak correlation between DIS and baseline impedance (r = -0.230, P < 0.05). "Baseline impedance > 1764 Ω" was an independent predictor for PPI failure (OR, 11.9; 95% CI, 2.4-58.9; P < 0.01). ConclusionsThe DIS and decreased baseline impedance was observed in patients with mucosa erosion or pathological acid reflux. The baseline impedance reflected the mucosal integrity, it was more sensitive to esophageal acid exposure. Patients with high impedance might not benefit from the PPI treatment.

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Gastroesophageal Reflux Might Cause Esophagitis Through a Cytokine-Mediated Mechanism Rather Than Caustic Acid Injury

Cited by 350 publications

References 35 publications

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

GPR84 and TREM-1 Signaling Contribute to the Pathogenesis of Reflux Esophagitis

Could proton pump inhibitors cause cancer?

Esophageal Baseline Impedance Reflects Mucosal Integrity and Predicts Symptomatic Outcome With Proton Pump Inhibitor Treatment

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