Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid

Sharma, Priya; Yadlapati, Rena

doi:10.1111/nyas.14501

Cited by 61 publications

(50 citation statements)

References 100 publications

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“…Since the mechanisms through which each gastric content affects the occurrence of LPRD differ, the cause of the disease may vary depending on the speci c re ux content and its mechanism of action. However, the common phenomenon exhibited by these four contents is that they release ROS [21]. In the current study, using an in vitro model of LPRD, we found that acid exposure signi cantly increased the expression of ROS and MMP, which was reduced following treatment with the antioxidant, NAC, an ROS inhibitor.…”

Section: Discussionsupporting

confidence: 44%

Matrix Metalloproteinase-7 Induces E-Cadherin Cleavage in Acid-Exposed Primary Human Pharyngeal Epithelial Cells Via The ROS/ERK/c-Jun Pathway

Kim

Jung

et al. 2021

Preprint

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Introduction Laryngopharyngeal reflux disease (LPRD) is caused by pharyngeal mucosal damage due to the reflux of gastric contents, including acid, pepsin, and bile juice. Our previous study has demonstrated that LPRD is associated with the cleavage of E-cadherin, which is facilitated by the acid-activated matrix metalloproteinase-7 (MMP-7); however, the mechanism by which the acid activates MMP-7 remains unclear. The purpose of this study was to investigate the mechanism by which MMP-7 is activated in the pharyngeal epithelial cells that are exposed to acid. Methods The levels of reactive oxygen species (ROS) were measured in the epithelial cells exposed to acid. To investigate the signaling mechanism of ROS in the expression of MMP-7, the mechanism of action of the mitogen-activated protein kinase was examined. The expression of various signaling factors were determined, according to the presence or absence of each inhibitor in the acid-exposed pharyngeal epithelial cells. To identify changes in the cleavage of E-cadherin, the integrity of the mucosal membrane was assessed using a transepithelial permeability test.ResultsWe found that acid exposure increased the levels of ROS, phosphorylated-extracellular signal-regulated kinase (p-ERK) 1/2, and phosphorylated-c-Jun (p-c-Jun) in pharyngeal epithelial cells. The ROS inhibitor reduced the expression of p-ERK and MMP-7, while the ERK inhibitor reduced the expression of p-c-Jun and MMP-7. Moreover, the c-Jun inhibitor reduced the expression of MMP-7 and blocked the degradation of E-cadherin. In addition, decrease in the levels of immunostained E-cadherin and increase in transepithelial permeability after acid exposure were collectively alleviated by the inhibitors of ROS, ERK, and c-Jun. Conclusions The degradation of E-cadherin that occurs after human mucosal cells are exposed to acid appears to be caused by an increase in the expression of MMP-7 via the ROS/ERK/c-Jun pathway, which is thought to be an important mechanism associated with the development of LPRD.

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Section: Discussionsupporting

confidence: 44%

Matrix Metalloproteinase-7 Induces E-Cadherin Cleavage in Acid-Exposed Primary Human Pharyngeal Epithelial Cells Via The ROS/ERK/c-Jun Pathway

Kim

Jung

et al. 2021

Preprint

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“…However, the efficacy of PPI therapy is lower for patients with esophageal symptoms of GERD, and wanes even further for patients with extra-esophageal symptoms of GERD such as LPR [ 28 ]. One explanation for suboptimal symptom response to acid suppression relates to the well-established fact that symptoms of GERD are not all related to acid [ 20 ]. Regurgitation is a symptom perceived due to the mechanical flow of refluxate, regardless of acidity.…”

Section: Discussionmentioning

confidence: 99%

“…Despite effectively suppressing gastric acid secretion, PPI therapy does not reduce the burden of gastroesophageal refluxate. Similar to concepts in gastroesophageal reflux disease (GERD), gastric refluxate is composed of bile and pepsin, which can injure esophageal and laryngeal epithelium, independent of acidity [ 20 ]. Thus, safe and less invasive treatment options beyond acid suppression are needed for LPR.…”

Section: Introductionmentioning

confidence: 99%

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux

et al. 2021

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Background The Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR). Methods This two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI. Results Thirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m 2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01). Conclusion This clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811).

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“…Almost all cases of esophageal adenocarcinoma arise from underlying Barrett's esophagus, a metaplastic change in the esophagus [163]. Moreover, central obesity is involved in the pathogenesis and progression of Barrett's esophagus to esophageal adenocarcinoma [164,165] and GERD, a disorder due to the retrograde flow of refluxate into the esophagus [166]. Barrett's esophagus, esophageal adenocarcinoma, and GERD thus might be associated with adipokine alterations.…”

Section: Esophagusmentioning

confidence: 99%

“…The alteration patterns might act as diagnostic markers or therapeutic targets for specific digestive diseases. [171,185,186], stronger in men [166,172] Adiponectin I/D/N [184]/Among patients with GERD and among smokers [181], especially in patients with GERD [180,182]/ [186] Esophageal cancer Leptin I…”

Section: Adiponectinmentioning

confidence: 99%

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression

Chang

Yang

2020

IJMS

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Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett’s esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

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Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid

Cited by 61 publications

References 100 publications

Matrix Metalloproteinase-7 Induces E-Cadherin Cleavage in Acid-Exposed Primary Human Pharyngeal Epithelial Cells Via The ROS/ERK/c-Jun Pathway

Matrix Metalloproteinase-7 Induces E-Cadherin Cleavage in Acid-Exposed Primary Human Pharyngeal Epithelial Cells Via The ROS/ERK/c-Jun Pathway

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression

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