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Samuels TL, Johnston N. Pepsin, Mucosal Injury, and Pathophysiology of Non-acid Reflux. Otolaryngol Clin North Am 2025; 58:415-432. [PMID: 40148170 DOI: 10.1016/j.otc.2025.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
The gastric enzyme pepsin is a critically under-addressed aggressor during reflux disease and is regarded by many as the most damaging element of laryngopharyngeal reflux. Research over the last 2 decades has elucidated mechanisms by which pepsin causes damage during weakly and nonacid reflux yielding information to exploit its diagnostic and therapeutic potential. These findings have driven advances that, while still in their infancy, harbor important clinical implications.
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Affiliation(s)
- Tina L Samuels
- Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
| | - Nikki Johnston
- Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
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Zhang T, Tang X. Untangling immune cell contributions in the progression from GERD to Barrett's esophagus and esophageal cancer: Insights from genetic causal analysis. Int Immunopharmacol 2025; 150:114271. [PMID: 39965389 DOI: 10.1016/j.intimp.2025.114271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/30/2025] [Accepted: 02/07/2025] [Indexed: 02/20/2025]
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is a rapidly increasing malignancy with significant morbidity and mortality. The progression from gastroesophageal reflux disease (GERD) to Barrett's esophagus (BE) and ultimately to EAC is thought to be influenced by chronic inflammation and immune cell dynamics. Despite the observed correlations in observational studies, the causal relationships between immune cell phenotypes and this disease continuum remain unclear. METHODS This study utilized a two-sample Mendelian Randomization (MR) approach to investigate the causal roles of 731 distinct immune cell phenotypes in the GERD-BE-EAC continuum. The analysis leveraged genome-wide association study (GWAS) data for immune phenotypes from a Sardinian cohort and data for GERD, BE, and EAC from the FinnGen and Open GWAS databases. A comprehensive set of MR methods, including inverse variance weighted (IVW), MR-Egger, and weighted median estimators, was employed to assess causality. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy, ensuring the robustness of the findings. RESULTS The study revealed complex and multifaceted roles of immune cells across the GERD-BE-EAC continuum. In GERD, 34 immune phenotypes were found to be causally associated with either increased or decreased risk. Protective effects were observed in phenotypes such as Unswitched Memory B cells, while others like CD45RA- CD4+ T cells were linked to an elevated risk. In the context of BE, 28 immune phenotypes demonstrated significant causal associations, with the majority being protective, including Unswitched Memory B cells and CD62L on Granulocytes. Conversely, certain phenotypes, such as CD24 on Transitional B cells, were identified as risk factors for BE. For EAC, 34 immune phenotypes were implicated, with various B cell subsets, particularly those expressing BAFF-R and CD24, associated with an increased risk, while Switched Memory B cells and specific myeloid cell phenotypes showed protective effects. CONCLUSIONS This study provides novel insights into the complex role of immune cells in the pathogenesis of EAC, revealing a dynamic interplay where certain immune phenotypes may be protective in early stages but become risk-enhancing in later stages of disease progression. These findings highlight the potential of immune cell phenotypes to serve as biomarkers for early detection and targeted therapeutic interventions across the GERD-BE-EAC continuum. Further research is warranted to validate these findings in diverse populations and to explore the underlying mechanisms driving these immune-mediated effects.
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Affiliation(s)
- Tai Zhang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University Health Science Center, Beijing 100091, China; Peking University Health Science Center, Beijing 100191, China
| | - Xudong Tang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Peking University Health Science Center, Beijing 100091, China; Institute of Digestive Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China.
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Argüero J, Sifrim D. Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management. Nat Rev Gastroenterol Hepatol 2024; 21:282-293. [PMID: 38177402 DOI: 10.1038/s41575-023-00883-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/28/2023] [Indexed: 01/06/2024]
Abstract
Gastro-oesophageal reflux disease (GERD) is a common gastrointestinal disorder in which retrograde flow of gastric content into the oesophagus causes uncomfortable symptoms and/or complications. It has a multifactorial and partially understood pathophysiology. GERD starts in the stomach, where the refluxate material is produced. Following the trajectory of reflux, the failure of the antireflux barrier, primarily the lower oesophageal sphincter and the crural diaphragm, enables the refluxate to reach the oesophageal lumen, triggering oesophageal or extra-oesophageal symptoms. Reflux clearance mechanisms such as primary and secondary peristalsis and the arrival of bicarbonate-rich saliva are critical to prevent mucosal damage. Alterations of the oesophageal mucosal integrity, such as macroscopic oesophagitis or microscopic changes, determine the perception of symptoms. The intensity of the symptoms is affected by peripheral and central neural and psychological mechanisms. In this Review, we describe an updated understanding of the complex and multifactorial pathophysiology of GERD. It is now recognized that different GERD phenotypes have different degrees of reflux, severity of mucosal integrity damage and type, and severity of symptoms. These variations are probably due to the occurrence of a predominant pathophysiological mechanism in each patient. We also describe the main pathophysiological mechanisms of GERD and their implications for personalized diagnosis and management.
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Affiliation(s)
- Julieta Argüero
- Neurogastroenterology section of Gastroenterology Department, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Daniel Sifrim
- Wingate Institute of Neurogastroenterology, Queen Mary University of London, London, UK.
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Samuels TL, Blaine‐Sauer S, Yan K, Johnston N. Amprenavir inhibits pepsin-mediated laryngeal epithelial disruption and E-cadherin cleavage in vitro. Laryngoscope Investig Otolaryngol 2023; 8:953-962. [PMID: 37621274 PMCID: PMC10446255 DOI: 10.1002/lio2.1102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 06/12/2023] [Indexed: 08/26/2023] Open
Abstract
Background Laryngopharyngeal reflux (LPR) causes chronic cough, throat clearing, hoarseness, and dysphagia and can promote laryngeal carcinogenesis. More than 20% of the US population suffers from LPR and there is no effective medical therapy. Pepsin is a predominant source of damage during LPR which disrupts laryngeal barrier function potentially via E-cadherin cleavage proteolysis and downstream matrix metalloproteinase (MMP) dysregulation. Fosamprenavir (FDA-approved HIV therapeutic and prodrug of amprenavir) is a pepsin-inhibiting LPR therapeutic candidate shown to rescue damage in an LPR mouse model. This study aimed to examine amprenavir protection against laryngeal monolayer disruption and related E-cadherin proteolysis and MMP dysregulation in vitro. Methods Laryngeal (TVC HPV) cells were exposed to buffered saline, pH 7.4 or pH 4 ± 1 mg/mL pepsin ± amprenavir (10-60 min). Analysis was performed by microscopy, Western blot, and real time polymerase chain reaction (qPCR). Results Amprenavir (1 μM) rescued pepsin acid-mediated cell dissociation (p < .05). Pepsin acid caused E-cadherin cleavage indicative of regulated intramembrane proteolysis (RIP) and increased MMP-1,3,7,9,14 24-h postexposure (p < .05). Acid alone did not cause cell dissociation or E-cadherin cleavage. Amprenavir (10 μM) protected against E-cadherin cleavage and MMP-1,9,14 induction (p < .05). Conclusions Amprenavir, at serum concentrations achievable provided the manufacturer's recommended dose of fosamprenavir for HIV, protects against pepsin-mediated cell dissociation, E-cadherin cleavage, and MMP dysregulation thought to contribute to barrier dysfunction and related symptoms during LPR. Fosamprenavir to amprenavir conversion by laryngeal epithelia, serum and saliva, and relative drug efficacies in an LPR mouse model are under investigation to inform development of inhaled formulations for LPR.
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Affiliation(s)
- Tina L. Samuels
- Department of Otolaryngology and Communication Sciences, Medical College of WisconsinMilwaukeeWisconsinUSA
| | - Simon Blaine‐Sauer
- Department of Otolaryngology and Communication Sciences, Medical College of WisconsinMilwaukeeWisconsinUSA
| | - Ke Yan
- Department of Pediatrics Quantitative Health Sciences, Medical College of WisconsinMilwaukeeWisconsinUSA
| | - Nikki Johnston
- Department of Otolaryngology and Communication Sciences, Medical College of WisconsinMilwaukeeWisconsinUSA
- Department of Microbiology and ImmunologyMedical College of WisconsinMilwaukeeWisconsinUSA
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Samuels TL, Blaine-Sauer S, Yan K, Plehhova K, Coyle C, Johnston N. Topical Alginate Protection against Pepsin-Mediated Esophageal Damage: E-Cadherin Proteolysis and Matrix Metalloproteinase Induction. Int J Mol Sci 2023; 24:ijms24097932. [PMID: 37175640 PMCID: PMC10178445 DOI: 10.3390/ijms24097932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Epithelial barrier dysfunction is a hallmark of gastroesophageal reflux disease (GERD) related to symptom origination, inflammatory remodeling and carcinogenesis. Alginate-based antireflux medications were previously shown to topically protect against peptic barrier disruption, yet the molecular mechanisms of injury and protection were unclear. Herein, Barrett's esophageal (BAR-T) cells were pretreated with buffered saline (HBSS; control), dilute alginate medications (Gaviscon Advance or Gaviscon Double Action, Reckitt Benckiser), a viscosity-matched placebo, or ADAM10 and matrix metalloproteinase (MMP) inhibitors before exposure to HBSS pH7.4 or pH4 ± 1 mg/mL pepsin for 10-60 min. Cell viability was assessed by ATP assay; mediators of epithelial integrity, E-cadherin, ADAM10, and MMPs were examined by Western blot and qPCR. Alginate rescued peptic reduction of cell viability (p < 0.0001). Pepsin-pH4 yielded E-cadherin fragments indicative of regulated intramembrane proteolysis (RIP) which was not rescued by inhibitors of known E-cadherin sheddases. Transcriptional targets of E-cadherin RIP fragments were elevated at 24 h (MMP-1,2,9,14; p < 0.01). Alginate rescued E-cadherin cleavage, ADAM10 maturation, and MMP induction (p < 0.01). Results support RIP as a novel mechanism of peptic injury during GERD. Alginate residue after wash-out to mimic physiologic esophageal clearance conferred lasting protection against pepsin-induced molecular mechanisms that may exacerbate GERD severity and promote carcinogenesis in the context of weakly acidic reflux.
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Affiliation(s)
- Tina L Samuels
- Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Simon Blaine-Sauer
- Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Ke Yan
- Department of Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | | | | | - Nikki Johnston
- Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Blaine-Sauer S, Samuels TL, Yan K, Johnston N. The Protease Inhibitor Amprenavir Protects against Pepsin-Induced Esophageal Epithelial Barrier Disruption and Cancer-Associated Changes. Int J Mol Sci 2023; 24:6765. [PMID: 37047737 PMCID: PMC10095080 DOI: 10.3390/ijms24076765] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/08/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) significantly impacts patient quality of life and is a major risk factor for the development of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). Proton pump inhibitors (PPIs) are the standard-of-care for GERD and are among the most prescribed drugs in the world, but do not protect against nonacid components of reflux such as pepsin, or prevent reflux-associated carcinogenesis. We recently identified an HIV protease inhibitor amprenavir that inhibits pepsin and demonstrated the antireflux therapeutic potential of its prodrug fosamprenavir in a mouse model of laryngopharyngeal reflux. In this study, we assessed the capacity of amprenavir to protect against esophageal epithelial barrier disruption in vitro and related molecular events, E-cadherin cleavage, and matrix metalloproteinase induction, which are associated with GERD severity and esophageal cancer. Herein, weakly acidified pepsin (though not acid alone) caused cell dissociation accompanied by regulated intramembrane proteolysis of E-cadherin. Soluble E-cadherin responsive matrix metalloproteinases (MMPs) were transcriptionally upregulated 24 h post-treatment. Amprenavir, at serum concentrations achievable given the manufacturer-recommended dose of fosamprenavir, protected against pepsin-induced cell dissociation, E-cadherin cleavage, and MMP induction. These results support a potential therapeutic role for amprenavir in GERD recalcitrant to PPI therapy and for preventing GERD-associated neoplastic changes.
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Affiliation(s)
- Simon Blaine-Sauer
- Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (S.B.-S.)
| | - Tina L. Samuels
- Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (S.B.-S.)
| | - Ke Yan
- Department of Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Nikki Johnston
- Department of Otolaryngology and Communication Science, Medical College of Wisconsin, Milwaukee, WI 53226, USA; (S.B.-S.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Samuels TL, Yan K, Patel N, Plehhova K, Coyle C, Hurley BP, Johnston N. Alginates for Protection Against Pepsin-Acid Induced Aerodigestive Epithelial Barrier Disruption. Laryngoscope 2022; 132:2327-2334. [PMID: 35238407 DOI: 10.1002/lary.30087] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 12/16/2022]
Abstract
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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Affiliation(s)
- Tina L Samuels
- Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A
| | - Ke Yan
- Pediatrics Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A
| | - Nishma Patel
- Reckitt Benckiser, Hull, England, United Kingdom
| | | | - Cathal Coyle
- Reckitt Benckiser, Hull, England, United Kingdom
| | - Bryan P Hurley
- Pediatrics, Mucosal Immunology & Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Nikki Johnston
- Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A.,Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A
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Zhang ML, Ran LQ, Wu MJ, Jia QC, Qin ZM, Peng YG. NF-κB: A novel therapeutic pathway for gastroesophageal reflux disease? World J Clin Cases 2022; 10:8436-8442. [PMID: 36157831 PMCID: PMC9453379 DOI: 10.12998/wjcc.v10.i24.8436] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 06/16/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
Although gastroesophageal reflux disease (GERD), a common chronic disease in clinical practice, has been widely studied, its potential adverse impact on patients is still a significant clinical concern. It is necessary to understand the pathogenesis of the disease and choose appropriate treatment according to its mechanism. The pathogenesis of GERD is diverse and complex. As the traditional treatment methods are expensive and ineffective in alleviating symptoms in some patients, new treatment options need to be explored. Our previous study suggested that the activation of nuclear factor-kappa beta (NF-κB) in esophageal mucosa may be related to the injury of epithelial barrier function caused by reflux. Based on the literature and our previous study results, it is speculated that inhibition of NF-κB activation may block the insult of GERD on the esophageal mucosal barrier. NF-κB may play an important role in the development of GERD. This article reviews the pathogenesis of GERD and the relationship between NF-κB and GERD, in order to provide new strategies for the treatment of GERD.
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Affiliation(s)
- Mao-Lin Zhang
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Long-Qing Ran
- Department of Anesthesia, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610019, China
| | - Meng-Jun Wu
- Department of Anesthesia, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610019, China
| | - Qin-Chen Jia
- Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Zhi-Ming Qin
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400042, China
| | - Yong G Peng
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
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Talbert S, Bourgault AM, Rathbun KP, Abomoelak B, Deb C, Mehta D, Sole ML. Pepsin A in Tracheal Secretions From Patients Receiving Mechanical Ventilation. Am J Crit Care 2021; 30:443-450. [PMID: 34719715 DOI: 10.4037/ajcc2021528] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
BACKGROUND In patients in the intensive care unit (ICU) receiving mechanical ventilation, aspiration of gastric contents may lead to ventilator-associated events and other adverse outcomes. Pepsin in pulmonary secretions is a biomarker of microaspiration of gastric contents. OBJECTIVES To evaluate the association between tracheal pepsin A and clinical outcomes related to ventilator use. METHODS A subset of 297 patients from a larger clinical trial on aspiration of oral secretions in adults receiving mechanical ventilation consented to have pepsin A measured in their tracheal aspirate samples. A concentration ≥6.25 ng/mL indicated a positive result. Abundant microaspiration was defined as pepsin A in ≥30% of samples. Statistical analyses included analysis of variance, analysis of covariance, and χ2 tests. RESULTS Most patients were White men, mean age 59.7 (SD, 18.8) years. Microaspiration was found in 43.8% of patients (n = 130), with abundant microaspiration detected in 17.5% (n = 52). After acuity was controlled for, patients with tracheal pepsin A had a longer mechanical ventilation duration (155 vs 104 hours, P < .001) and ICU stay (9.9 vs 8.2 days, P = .04), but not a longer hospital stay. CONCLUSIONS Microaspiration of gastric contents occurred in nearly half of patients and was associated with a longer duration of mechanical ventilation and a longer stay in the ICU. Additional preventative interventions beyond backrest elevation, oropharyngeal suctioning, and management of endotracheal tube cuff pressure may be needed. Also, the timing of pepsin measurements to capture all microaspiration events requires additional exploration.
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Affiliation(s)
- Steven Talbert
- Steven Talbert is interim director of the nursing PhD program and a clinical assistant professor, University of Central Florida College of Nursing, Orlando, Florida
| | - Annette M. Bourgault
- Annette M. Bourgault is an associate professor, University of Central Florida College of Nursing and a nurse scientist, Orlando Health, Orlando, Florida
| | - Kimberly Paige Rathbun
- Kimberly Paige Rathbun is a graduate research assistant, University of Central Florida College of Nursing
| | - Bassam Abomoelak
- Bassam Abomoelak is a senior research associate, Pediatric Specialty Diagnostic Laboratory, Arnold Palmer Hospital, Orlando, Florida
| | - Chirajyoti Deb
- Chirajyoti Deb is a senior research associate, Pediatric Specialty Diagnostic Laboratory
| | - Devendra Mehta
- Devendra Mehta is a pediatric gastroenterologist, Pediatric Specialty Diagnostic Laboratory
| | - Mary Lou Sole
- Mary Lou Sole is dean, professor, and Orlando Health Endowed Chair in Nursing, University of Central Florida College of Nursing and clinical scientist, Orlando Health
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Ergün P, Capanoglu D, Kipcak S, Bor S. Response of Esophageal Epithelium to Acute and Chronic Stress in Rabbits. Bull Exp Biol Med 2021; 171:582-587. [PMID: 34617182 DOI: 10.1007/s10517-021-05273-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Indexed: 12/17/2022]
Abstract
We studied electrophysiological changes in rabbit esophageal epithelium following acute (AS) and chronic stress (CS). Esophageal tissue was placed in Ussing chamber and the potential difference U between the luminal and abluminal sides, the short-circuit current Isc, as well as the tissue resistance R were measured. The initial values of these parameters for each sample were determined after the samples were stabilized in Ringer solution. Then, the tissues were exposed for 1 h to normal Ringer solution or Ringer solution with pH 4.0 and pH 1.7 with or without pepsin (0.25 mg/ml). Fluorescein was added to the luminal side of the sample to measure its permeability. In the AS group, U at Ringer solution (pH 1.7)+pepsin was significantly decreased in comparison with the baseline and control values (by 46 and 22%, respectively, p<0.05). R decreased by 74% in comparison with baseline, which little differed from the decrease in control samples exposed to Ringer solution (pH 1.7)+pepsin (by 62%). CS did not change U relative to baseline values, while changes in R were similar to those in the AS group. In the AS group, the permeability of the esophageal tissue perfused with Ringer solution (pH 1.7)+pepsin was significantly higher than in both the control and CS groups. AS, but not CS, made the esophageal epithelium more sensitive to the effects of noxious agents, disrupted barrier properties, and increased permeability. The effects of stress on gastroesophageal reflux disease symptoms can be related to severe exposure to acid and/or pepsin; however, the mechanisms other than epithelial defense should be evaluated.
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Affiliation(s)
- P Ergün
- Ege Reflux Study Group, Division of Gastroenterology, Izmir, Turkey.,Department of Medical Biochemistry, Izmir, Turkey
| | - D Capanoglu
- Ege Reflux Study Group, Division of Gastroenterology, Izmir, Turkey
| | - S Kipcak
- Ege Reflux Study Group, Division of Gastroenterology, Izmir, Turkey.,Department of Medical Biology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - S Bor
- Ege Reflux Study Group, Division of Gastroenterology, Izmir, Turkey.
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Basnayake C, Geeraerts A, Pauwels A, Koek G, Vaezi M, Vanuytsel T, Tack J. Systematic review: duodenogastroesophageal (biliary) reflux prevalence, symptoms, oesophageal lesions and treatment. Aliment Pharmacol Ther 2021; 54:755-778. [PMID: 34313333 DOI: 10.1111/apt.16533] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 05/20/2021] [Accepted: 07/01/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND The prevalence of duodenogastroesophageal reflux (DGER) and its effect on symptoms and oesophageal lesions in gastroesophageal reflux disease (GERD) is unclear. AIMS To conduct a systematic review to determine the prevalence of DGER among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. METHODS We searched Pubmed and MEDLINE for full text, English language articles until October 2020 that evaluated DGER prevalence among patients with GERD, the effect of DGER on symptoms and oesophageal lesions, and the treatment of DGER. RESULTS We identified 3891 reports and included 35 which analysed DGER prevalence in GERD, 15 which evaluated its effect in non-erosive reflux disease (NERD), 17 on erosive oesophagitis, 23 in Barrett's, and 13 which evaluated the treatment of DGER. The prevalence of DGER, when evaluated by Bilitec, among all GERD patients ranged from 10% to 97%, in NERD 10%-63%, in erosive oesophagitis 22%-80% and in Barrett's 50%-100%. There were no differences in the presence or degree of DGER among patients who were asymptomatic or symptomatic on proton pump inhibitors (PPI). The most commonly evaluated treatments for DGER were PPIs and DGER reduced post-PPI therapy in all studies. CONCLUSIONS The prevalence of DGER increased with more advanced oesophageal lesions and did not explain persisting symptoms among patients taking PPI therapy. PPIs appear to be effective in the treatment of DGER. DGER remains an important consideration in patients with GERD and future therapies deserve more study.
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Affiliation(s)
- Chamara Basnayake
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium.,St Vincent's Hospital & University of Melbourne, Melbourne, VIC, Australia
| | - Annelies Geeraerts
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ans Pauwels
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ger Koek
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Michael Vaezi
- Vanderbilt University Medical Center, Nashville, TN, USA
| | - Tim Vanuytsel
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Jan Tack
- Department of Chronic Diseases, Metabolism and Ageing (ChroMetA), Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
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Oldfield EC, Parekh PJ, Johnson DA. Diagnosis and Treatment of Esophageal Chest Pain. THE ESOPHAGUS 2021:18-37. [DOI: 10.1002/9781119599692.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Abdulnour-Nakhoul SM, Nakhoul NL. Ussing Chamber Methods to Study the Esophageal Epithelial Barrier. Methods Mol Biol 2021; 2367:215-233. [PMID: 32946026 DOI: 10.1007/7651_2020_324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
The Ussing chamber was developed in 1949 by Hans Ussing and quickly became a powerful tool to study ion and solute transport in epithelia. The chamber has two compartments strictly separating the apical and basolateral sides of the tissue under study. The two sides of the tissue are connected via electrodes to a modified electrometer/pulse generator that allows measurement of electrical parameters, namely, transepithelial voltage, current, and resistance. Simultaneously, permeability of the tissue to specific solutes or markers can be monitored by using tracers or isotopes to measure transport from one side of the tissue to the other. In this chapter, we will describe the use of the Ussing chamber to study the barrier properties of the mouse esophageal epithelium. We will also briefly describe the use of the modified Ussing chamber to simultaneously study transepithelial and cellular electrophysiology in the rabbit esophageal epithelium. Lastly, we will cover the use of the Ussing chamber to study bicarbonate secretion in the pig esophagus. These examples highlight the versatility of the Ussing chamber technique in investigating the physiology and pathophysiology of epithelia including human biopsies.
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Affiliation(s)
| | - Nazih L Nakhoul
- Departments of Medicine and Physiology, Tulane University School of Medicine, New Orleans, LA, USA
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14
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Grobman M. Aerodigestive Disease in Dogs. Vet Clin North Am Small Anim Pract 2020; 51:17-32. [PMID: 33131915 DOI: 10.1016/j.cvsm.2020.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aerodigestive disorders (AeroDs) in people encompass a wide range of clinical syndromes, reflecting the complex relationship between the respiratory and digestive tracts. In veterinary medicine, aspiration is used interchangeably with aspiration pneumonia. Although aspiration pneumonia is a common disorder in dogs, it does not reflect the breadth of AeroDs. Unfortunately, AeroDs rarely are investigated in veterinary medicine because of lack of clinical recognition, limitations in available diagnostics, and the fact that AeroDs may be caused by occult digestive disease. Recognizing patients with AerodD represents an area of significant clinical importance that may provide additional areas of clinical intervention.
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Affiliation(s)
- Megan Grobman
- Auburn University, Department of Clinical Sciences, 1220 Wire Road, Auburn, AL 36849, USA.
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15
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Sharma P, Yadlapati R. Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid. Ann N Y Acad Sci 2020; 1486:3-14. [PMID: 33015827 DOI: 10.1111/nyas.14501] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/24/2020] [Accepted: 09/01/2020] [Indexed: 12/14/2022]
Abstract
Gastroesophageal reflux disease (GERD) is a disorder due to the retrograde flow of refluxate into the esophagus. Although GERD is a common clinical diagnosis, its pathogenesis is quite complex. As a result of its multifactorial development, many patients continue to experience adverse symptoms due to GERD despite prolonged acid suppression with proton pump inhibitor therapy. The pathogenesis of GERD involves an interplay of chemical, mechanical, psychologic, and neurologic mechanisms, which contribute to symptom presentation, diagnosis, and treatment. As such, GERD should be approached as a disorder beyond acid. This review will investigate the major factors that contribute to the development of GERD, including factors related to the refluxate, esophageal defenses, and factors that promote pathologic reflux into the esophagus. In reviewing GERD pathogenesis, this paper will highlight therapeutic advances, with mention of future opportunities of study when approaching GERD.
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Affiliation(s)
- Priya Sharma
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Rena Yadlapati
- Division of Gastroenterology, University of California San Diego School of Medicine, Center for Esophageal Diseases, La Jolla, California
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16
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Nakhoul NL, Tu CL, Brown KL, Islam MT, Hodges AG, Abdulnour-Nakhoul SM. Calcium-sensing receptor deletion in the mouse esophagus alters barrier function. Am J Physiol Gastrointest Liver Physiol 2020; 318:G144-G161. [PMID: 31709833 PMCID: PMC6985844 DOI: 10.1152/ajpgi.00021.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Calcium-sensing receptor (CaSR) is the molecular sensor by which cells respond to small changes in extracellular Ca2+ concentrations. CaSR has been reported to play a role in glandular and fluid secretion in the gastrointestinal tract and to regulate differentiation and proliferation of skin keratinocytes. CaSR is present in the esophageal epithelium, but its role in this tissue has not been defined. We deleted CaSR in the mouse esophagus by generating keratin 5 CreER;CaSRFlox+/+compound mutants, in which loxP sites flank exon 7 of CaSR gene. Recombination was initiated with multiple tamoxifen injections, and we demonstrated exon 7 deletion by PCR analysis of genomic DNA. Quantitative real-time PCR and Western blot analyses showed a significant reduction in CaSR mRNA and protein expression in the knockout mice (EsoCaSR-/-) as compared with control mice. Microscopic examination of EsoCaSR-/- esophageal tissues showed morphological changes including elongation of the rete pegs, abnormal keratinization and stratification, and bacterial buildup on the luminal epithelial surface. Western analysis revealed a significant reduction in levels of adherens junction proteins E-cadherin and β catenin and tight junction protein claudin-1, 4, and 5. Levels of small GTPase proteins Rac/Cdc42, involved in actin remodeling, were also reduced. Ussing chamber experiments showed a significantly lower transepithelial resistance in knockout (KO) tissues. In addition, luminal-to-serosal-fluorescein dextran (4 kDa) flux was higher in KO tissues. Our data indicate that CaSR plays a role in regulating keratinization and cell-cell junctional complexes and is therefore important for the maintenance of the barrier function of the esophagus.NEW & NOTEWORTHY The esophageal stratified squamous epithelium maintains its integrity by continuous proliferation and differentiation of the basal cells. Here, we demonstrate that deletion of the calcium-sensing receptor, a G protein-coupled receptor, from the basal cells disrupts the structure and barrier properties of the epithelium.
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Affiliation(s)
- Nazih L. Nakhoul
- 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana,2Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chia-Ling Tu
- 3Endocrine Unit, Veterans Affairs Medical Center, University of California, San Francisco, California
| | - Karen L. Brown
- 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana,2Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana
| | - M. Toriqul Islam
- 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana,2Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Anna G. Hodges
- 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana,2Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana
| | - Solange M. Abdulnour-Nakhoul
- 1Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana,2Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana,4Southeast Louisiana Veterans Health Care System, New Orleans, Louisiana
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17
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Wound healing after tonsillectomy - a review of the literature. The Journal of Laryngology & Otology 2018; 132:764-770. [PMID: 30289104 DOI: 10.1017/s002221511800155x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To summarise the available literature related to wound healing post tonsillectomy, including the stages of healing, experimental models for assessing healing (in animals and humans) and the various factors that affect wound healing. METHODS A search of the English literature was conducted using the Ovid Medline database, with the search terms 'tonsillectomy' or 'tonsil' and 'wound healing'. Thirty-one articles that objectively assessed tonsillectomy wound healing were included for analysis. RESULTS The majority of assessments in humans investigating tonsillectomy wound healing involve serial direct clinical examinations of the oral cavity. Many patient and surgical factors have been shown to affect wound healing after tonsillectomy. There is some research to suggest that the administration of adjunctive treatment in the post-operative period may be beneficial to tonsillectomy wound healing. CONCLUSION Wound healing post tonsillectomy has been poorly researched. Having a better understanding of the process of wound healing would allow surgeons to potentially prevent, anticipate and manage complications from the surgery that arise as part of the healing process.
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18
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Choksi Y, Lal P, Slaughter JC, Sharda R, Parnell J, Higginbotham T, Vaezi MF. Esophageal Mucosal Impedance Patterns Discriminate Patients With Eosinophilic Esophagitis From Patients With GERD. Clin Gastroenterol Hepatol 2018; 16:664-671.e1. [PMID: 29248733 DOI: 10.1016/j.cgh.2017.12.020] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 12/03/2017] [Accepted: 12/08/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS It is a challenge to make a diagnosis of eosinophilic esophagitis (EoE) because its symptoms and histologic features overlap with those of gastroesophageal reflux disease (GERD). A minimally invasive device was recently developed to detect mucosal impedance (MI) that measures epithelial integrity during upper endoscopy. We aimed to quantify MI along the esophagus and identify patterns that differentiated patients with and without GERD from those with EoE, and determine whether MI values and patterns are sufficient to identify patients with EoE using histologic findings as a reference. METHODS We performed a retrospective analysis of 91 patients with upper gastrointestinal symptoms referred for diagnostic testing for GERD and EoE from 2012 through 2014 (discovery set). During the first endoscopy, MI measurements were obtained at 2, 5, and 10 cm from the squamocolumnar junction. GERD was confirmed by ambulatory pH tests, and histologic analyses of biopsies were used to confirm EoE. We then used statistical modeling to identify MI patterns along the esophagus (at 10 cm, 5 cm, and 2 cm) that associated with GERD vs EoE. We validated our findings in a prospective cohort of 49 patients undergoing elective upper endoscopy for dysphagia, from 2015 through 2016, testing the ability of MI patterns to identify patients with vs. without EoE. RESULTS We found patients with EoE to have a unique MI pattern, with low values along the esophageal axis. MI measurements at 5 cm could discern patients with normal vs abnormal mucosa with 83% sensitivity and 79% specificity, and patients with EoE vs GERD with 84% sensitivity and 70% specificity; these measurements differentiated the patient populations with the highest level of accuracy of any of the 6 measurements tested. In the validation study, a rater using the esophageal MI pattern identified patients with EoE with 100% sensitivity and 96% specificity. CONCLUSION We identified and validated a pattern of MI along the esophagus that can identify patients with EoE vs normal mucosa or GERD with high levels of sensitivity.
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Affiliation(s)
- Yash Choksi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Pooja Lal
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Rohit Sharda
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Jacob Parnell
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Tina Higginbotham
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee.
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19
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Jamilah I, Priyani N, Natalia SL. Viability of lactic acid bacteria coated as synbiotic during storage and gastro-intestinal simulation. ACTA ACUST UNITED AC 2018. [DOI: 10.1088/1755-1315/130/1/012014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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20
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Hunt EB, Sullivan A, Galvin J, MacSharry J, Murphy DM. Gastric Aspiration and Its Role in Airway Inflammation. Open Respir Med J 2018; 12:1-10. [PMID: 29456774 PMCID: PMC5806178 DOI: 10.2174/1874306401812010001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/22/2017] [Accepted: 01/01/2018] [Indexed: 12/15/2022] Open
Abstract
Gastro-Oesophageal Reflux (GOR) has been associated with chronic airway diseases while the passage of foreign matter into airways and lungs through aspiration has the potential to initiate a wide spectrum of pulmonary disorders. The clinical syndrome resulting from such aspiration will depend both on the quantity and nature of the aspirate as well as the individual host response. Aspiration of gastric fluids may cause damage to airway epithelium, not only because acidity is toxic to bronchial epithelial cells but also due to the effect of digestive enzymes such as pepsin and bile salts. Experimental models have shown that direct instillation of these factors to airways epithelia cause damage with a consequential inflammatory response. The pathophysiology of these responses is gradually being dissected, with better understanding of acute gastric aspiration injury, a major cause of acute lung injury, providing opportunities for therapeutic intervention and potentially, ultimately, improved understanding of the chronic airway response to aspiration. Ultimately, clarification of the inflammatory pathways which are related to micro-aspiration via pepsin and bile acid salts may eventually progress to pharmacological intervention and surgical studies to assess the clinical benefits of such therapies in driving symptom improvement or reducing disease progression.
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Affiliation(s)
- E B Hunt
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.,The Health Research Board Clinical Research Facility, University College Cork, Cork, Ireland
| | - A Sullivan
- The APC Microbiome Institute, Schools of Medicine and Microbiology, University College Cork, Ireland
| | - J Galvin
- The APC Microbiome Institute, Schools of Medicine and Microbiology, University College Cork, Ireland
| | - J MacSharry
- The APC Microbiome Institute, Schools of Medicine and Microbiology, University College Cork, Ireland
| | - D M Murphy
- The Department of Respiratory Medicine, Cork University Hospital, Cork, Ireland.,The Health Research Board Clinical Research Facility, University College Cork, Cork, Ireland
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21
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Hong SJ, Park SH, Moon JS, Shin WG, Kim JG, Lee YC, Lee DH, Jang JY, Kim JJ, Lee HL, Lee SW, Hwangbo Y, Xu J, Wang B, Xue Z, Liu F, Yuan Y, Leelakusolvong S, Dy F. The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study. Gut Liver 2017; 10:910-916. [PMID: 27282265 PMCID: PMC5087930 DOI: 10.5009/gnl15537] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 01/02/2016] [Accepted: 01/02/2016] [Indexed: 12/13/2022] Open
Abstract
Background/Aims To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. Methods A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. Results The mean decreases in the total symptom score at 4 weeks were estimated to be -18.1±13.8 in the combination therapy group and -15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were -8.4±6.6 in the combination therapy group and -6.8±5.9 in the monotherapy group (p=0.009). Conclusions Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.
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Affiliation(s)
- Su Jin Hong
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Soo-Heon Park
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Jeong Seop Moon
- Department of Internal Medicine, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Woon Geon Shin
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, Korea
| | - Jae Gyu Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jae J Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hang-Lak Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Sang Woo Lee
- Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Young Hwangbo
- Department of Preventive Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jianming Xu
- Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei, China
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China
| | - Zhanxiong Xue
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, China
| | - Fei Liu
- Department of Gastroenterology, Shanghai East Hospital, Tongji University, Shanghi, China
| | - Yaozong Yuan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghi, China
| | - Somchai Leelakusolvong
- Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Frederick Dy
- Department of Internal Medicine, University of Santo Tomas Hospital, Manila, Philippines
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22
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Kavitt RT, Lal P, Yuksel ES, Ates F, Slaughter JC, Garrett CG, Higginbotham T, Vaezi MF. Esophageal Mucosal Impedance Pattern is Distinct in Patients With Extraesophageal Reflux Symptoms and Pathologic Acid Reflux. J Voice 2017; 31:347-351. [DOI: 10.1016/j.jvoice.2016.06.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/27/2016] [Accepted: 06/30/2016] [Indexed: 12/12/2022]
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Wang L, Tan JJ, Wu T, Zhang R, Wu JN, Zeng FF, Liu YL, Han XY, Li YF, Li XP. Association between Laryngeal Pepsin Levels and the Presence of Vocal Fold Polyps. Otolaryngol Head Neck Surg 2016; 156:144-151. [PMID: 28045635 DOI: 10.1177/0194599816676471] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Objective To determine whether pepsin, the main component of refluxed gastric contents, is significantly associated with vocal fold polyps and to evaluate the diagnostic value of pepsin in vocal fold polyps’ tissues. Study Design Cross-sectional study. Setting Nanfang Hospital of Southern Medical University. Subjects and Methods The study included 32 patients with vocal fold polyps and 16 healthy controls between 2011 and 2012. Reflux symptom index and reflux finding score assessments, 24-hour combined multichannel intraluminal impedance and pH monitoring, and biopsy of the vocal fold polyp tissues or posterior laryngeal mucosa (healthy controls) for immunohistochemical pepsin staining were performed. Results The expression of pepsin was significantly higher in patients with vocal fold polyps than in controls (28/32, 75% vs 5/16, 31.25%; P < .001). The pepsin levels were significantly positively correlated with upright position pharyngeal acid reflux and esophageal reflux parameters adjusted by age. Based on pepsin staining data, the sensitivity and negative predictive values of 24-hour pH monitoring, the reflux symptom index, and the reflux finding score were 70% to 84.62%, whereas their specificity and positive predictive values were relatively low (20%-31.58%). Conclusion Pepsin reflux may be a risk factor for vocal fold polyps formation. In addition, pepsin immunohistochemical analysis of polyp biopsy samples appears to be a more sensitive and effective test for diagnosing laryngopharyngeal reflux than the reflux symptom index, the reflux finding score, and 24-hour pH monitoring in a clinical setting.
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Affiliation(s)
- Lu Wang
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia-Jie Tan
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ting Wu
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rui Zhang
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jia-Nuan Wu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fang-Fang Zeng
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - You-Li Liu
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-Yan Han
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan-Fei Li
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiang-Ping Li
- Department of Otolaryngology–Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Gaddam S, Sathyamurthy A, Kushnir V, Drapekin J, Sayuk G, Gyawali CP. Changes in symptom reflux association using dynamic pH thresholds during ambulatory pH monitoring: an observational cross-sectional study. Dis Esophagus 2016; 29:1013-1019. [PMID: 26471871 DOI: 10.1111/dote.12423] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Symptom reflux association (SRA) assesses symptoms associated with reflux events defined by pH <4.0, but limited symptoms associate with reflux events. We evaluated the impact of alternate pH thresholds on SRA in a large ambulatory pH database. Acid exposure time (AET), reflux events, and associated symptoms (within 2 minutes following a reflux event) were extracted from ambulatory pH studies performed off antireflux therapy (722 patients, 49.1 ± 0.5 years, 66.8% F) over a 7-year period. Symptom association probability (SAP) and symptom index (SI) were calculated at pH 3.5, 4.0, 4.5, and 5. Receiver operating characteristics (ROC) were generated using SRA at any pH as gold standard; areas under the curve (AUCs) were determined. Discordant cases were reanalyzed to determine changes in SRA and predictors of change using multivariate regression. At pH 4.0, 41% had a positive SAP, and 34% had a positive SI. While there was sustained gain in SI positivity from acidic to more weakly acidic pH thresholds, SAP positivity was highest at pH 4.5. On ROC analysis, performance characteristics were best at pH 4.0 (AUC 0.97) for SAP, and at pH 4.5 and 5.0 (AUC 0.92-0.94) for SI. On multivariate logistic regression adjusting for age, gender, and change in AET and reflux events, only number of associated symptoms predicted change in SRA (P < 0.0001). Changing pH thresholds for reflux events augments SRA by increasing reflux events associated with existing symptoms, while symptom recording remains the principal determinant of SRA.
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Affiliation(s)
- S Gaddam
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA
| | - A Sathyamurthy
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA
| | - V Kushnir
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA
| | - J Drapekin
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA
| | - G Sayuk
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA.,Division of Gastroenterology, Veterans Affairs Medical Center, St. Louis, USA
| | - C P Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA
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25
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Capanoglu D, Coskunsever D, Olukman M, Ülker S, Bor S. Esophageal Epithelial Resistance and Lower Esophageal Sphincter Muscle Contraction Increase in a Chronic Diabetic Rabbit Model. Dig Dis Sci 2016; 61:1879-87. [PMID: 26972084 DOI: 10.1007/s10620-016-4111-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 03/03/2016] [Indexed: 01/10/2023]
Abstract
BACKGROUND Esophageal motility disorders and possibly gastroesophageal reflux disease are common in patients with diabetes mellitus. AIMS We aimed to investigate both the electrophysiological characteristics of the esophageal epithelium and the contractility of the lower esophageal sphincter (LES) muscle in alloxane-induced diabetic rabbits. METHODS Electrophysiological properties were measured using an Ussing chamber method. An acid-pepsin model was employed with pH 1.7 or weakly acidic (pH 4) Ringer and/or pepsin. Smooth muscle strips of the LES were mounted in an isolated organ bath. Contractile responses to an electrical field stimulation and cumulative concentrations of acetylcholine were recorded. Contractility of the muscle strips were tested in the presence of Rho-kinase inhibitor (Y-27632) and nonspecific nitric oxide inhibitor (L-NAME). RESULTS The resistance of diabetic tissue perfused in the pH 1.7 Ringer decreased 17 %; pepsin addition decreased it by 49 %. The same concentrations caused a more distinct loss of resistance in the control tissues (22 and 76 %, p < 0.05). The perfusion of tissues in increased concentrations of luminal and serosal glucose did not change the tissue resistance and voltage. Diabetes significantly increased both the electrical field stimulation and acetylcholine-induced contractions in the LES muscle strips (p < 0.01). Incubation with Y-27632 significantly decreased the acetylcholine-induced contractions in a concentration-dependent manner (p < 0.01). CONCLUSIONS The acid-pepsin model in the diabetic rabbit esophageal tissue had less injury compared with the control. The diabetic rabbit LES muscle had higher contractility, possibly because of the activation of the Rho-Rhokinase pathway. Our results show that in a chronic diabetic rabbit model the esophagus resists reflux by activating mechanisms of mucosal defense and increasing the contractility of the LES.
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Affiliation(s)
- Doga Capanoglu
- Ege Reflux Group, Section of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Ege University, Bornova, 35100, Izmir, Turkey
| | - Deniz Coskunsever
- Department of Medical Pharmacology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Murat Olukman
- Department of Medical Pharmacology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Sibel Ülker
- Department of Medical Pharmacology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Serhat Bor
- Ege Reflux Group, Section of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Ege University, Bornova, 35100, Izmir, Turkey.
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Laczkó D, Rosztóczy A, Birkás K, Katona M, Rakonczay Z, Tiszlavicz L, Róka R, Wittmann T, Hegyi P, Venglovecz V. Role of ion transporters in the bile acid-induced esophageal injury. Am J Physiol Gastrointest Liver Physiol 2016; 311:G16-G31. [PMID: 27198194 DOI: 10.1152/ajpgi.00159.2015] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 04/20/2016] [Indexed: 01/31/2023]
Abstract
Barrett's esophagus (BE) is considered to be the most severe complication of gastro-esophageal reflux disease (GERD), in which the prolonged, repetitive episodes of combined acidic and biliary reflux result in the replacement of the squamous esophageal lining by columnar epithelium. Therefore, the acid-extruding mechanisms of esophageal epithelial cells (EECs) may play an important role in the defense. Our aim was to identify the presence of acid/base transporters on EECs and to investigate the effect of bile acids on their expressions and functions. Human EEC lines (CP-A and CP-D) were acutely exposed to bile acid cocktail (BAC) and the changes in intracellular pH (pHi) and Ca(2+) concentration ([Ca(2+)]i) were measured by microfluorometry. mRNA and protein expression of ion transporters was investigated by RT-PCR, Western blot, and immunohistochemistry. We have identified the presence of a Na(+)/H(+) exchanger (NHE), Na(+)/HCO3 (-) cotransporter (NBC), and a Cl(-)-dependent HCO3 (-) secretory mechanism in CP-A and CP-D cells. Acute administration of BAC stimulated HCO3 (-) secretion in both cell lines and the NHE activity in CP-D cells by an inositol triphosphate-dependent calcium release. Chronic administration of BAC to EECs increased the expression of ion transporters compared with nontreated cells. A similar expression pattern was observed in biopsy samples from BE compared with normal epithelium. We have shown that acute administration of bile acids differently alters ion transport mechanisms of EECs, whereas chronic exposure to bile acids increases the expression of acid/base transporters. We speculate that these adaptive processes of EECs represent an important mucosal defense against the bile acid-induced epithelial injury.
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Affiliation(s)
- Dorottya Laczkó
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary; First Department of Medicine, University of Szeged, Szeged, Hungary
| | - András Rosztóczy
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Klaudia Birkás
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Máté Katona
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary
| | - Zoltán Rakonczay
- First Department of Medicine, University of Szeged, Szeged, Hungary; Department of Pathophysiology, University of Szeged, Szeged, Hungary
| | | | - Richárd Róka
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Tibor Wittmann
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Péter Hegyi
- First Department of Medicine, University of Szeged, Szeged, Hungary; MTA-SZTE Translational Gastroenterology Research Group, University of Szeged, Szeged, Hungary; and Institute for Translational Medicine and First Department of Medicine, University of Pécs, Pécs, Hungary
| | - Viktória Venglovecz
- Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary;
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Dunbar KB, Agoston AT, Odze RD, Huo X, Pham TH, Cipher DJ, Castell DO, Genta RM, Souza RF, Spechler SJ. Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes. JAMA 2016; 315:2104-12. [PMID: 27187303 PMCID: PMC5030713 DOI: 10.1001/jama.2016.5657] [Citation(s) in RCA: 172] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
IMPORTANCE The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid. OBJECTIVE To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis. DESIGN, SETTING, AND PARTICIPANTS Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015. INTERVENTIONS PPIs stopped for 2 weeks. MAIN OUTCOMES AND MEASURES Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity). RESULTS At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P = .005] and 2 weeks [P = .002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; Δ, 16.2% [95% CI, 4.4%-26.5%], P = .005), mucosal impedance decreased (mean: 2671.3 Ω at baseline to 1508.4 Ω at 2 weeks; Δ, 1162.9 Ω [95% CI, 629.9-1695.9], P = .001), and all patients had evidence of esophagitis. CONCLUSIONS AND RELEVANCE In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01733810.
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Affiliation(s)
- Kerry B. Dunbar
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Agoston T. Agoston
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Robert D. Odze
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Xiaofang Huo
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Thai H. Pham
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Daisha J. Cipher
- College of Nursing and Health Innovation, University of Texas at Arlington, TX
| | - Donald O. Castell
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Robert M. Genta
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Pathology, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Miraca Life Sciences, Irving, TX
| | - Rhonda F. Souza
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Stuart J. Spechler
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
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Honda J, Iijima K, Asanuma K, Ara N, Shiroki T, Kondo Y, Hatta W, Uno K, Asano N, Koike T, Shimosegawa T. Estrogen Enhances Esophageal Barrier Function by Potentiating Occludin Expression. Dig Dis Sci 2016; 61:1028-1038. [PMID: 26660903 DOI: 10.1007/s10620-015-3980-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/24/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND We recently demonstrated that a female sex hormone, estrogen, suppressed esophageal epithelial injury in a reflux esophagitis model of rat, suggesting that estrogen may play an important role in controlling the progress of the gastro-esophageal reflux disease spectrum. However, the precise mechanism of the action is unclear. AIM To investigate the potential role of estrogen in the esophageal barrier function. METHODS Male rabbits were pretreated with either continuous release 17β-estradiol or placebo, and the excised esophageal mucosa was subjected to Ussing chamber experiments after the 2-week pre-treatment. The mucosal side of the chamber was perfused with luminal irritants (HCl or acidified sodium nitrite), while the basal side was perfused by modified Krebs buffer. The epithelial barrier function was evaluated by the transmembrane resistance and the epithelial permeability. The intercellular space of the epithelium was investigated with transmission electron microscopy and the expression of tight junction protein, occludin, claudin-1, and claudin-4, with immunoblotting. RESULTS Estrogen pre-treatment significantly attenuated the decrease in the transmembrane resistance and the increase in the epithelial permeability induced by luminal irritants. Furthermore, the dilation of the intercellular space induced by luminal HCl was significantly alleviated by 17β-estradiol administration. The baseline occludin expression was significantly potentiated by 17β-estradiol administration. CONCLUSIONS This is the first study showing an enhancement of the esophageal barrier function by 17β-estradiol administration. The lack of the protective effect of estrogen could be responsible for the male predominance of erosive reflux esophagitis.
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Affiliation(s)
- Junya Honda
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Katsunori Iijima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan.
| | - Kiyotaka Asanuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Nobuyuki Ara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Takeharu Shiroki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Yutaka Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Waku Hatta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Kaname Uno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
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Min YW, Choi K, Pyo JH, Son HJ, Rhee PL. Impaired Esophageal Mucosal Integrity May Play a Causative Role in Patients With Nongastroesophageal Reflux Disease-Related Noncardiac Chest Pain. Medicine (Baltimore) 2015; 94:e2295. [PMID: 26705212 PMCID: PMC4697978 DOI: 10.1097/md.0000000000002295] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Baseline impedance (BI) measurement can be used to evaluate the status of the esophageal mucosa integrity. We hypothesized that impaired esophageal mucosal integrity may play a causative role in patients with nongastroesophageal reflux disease (non-GERD)-related noncardiac chest pain (NCCP). This retrospective study analyzed 24-hour multichannel intraluminal impedance-pH testing data from 77 patients with NCCP and 5 healthy volunteers. BI was calculated at 3 cm (distal esophagus) and 17 cm (proximal esophagus) above the lower esophageal sphincter. GERD was defined by the presence of pathologic acid exposure or reflux esophagitis. Among the 77 patients with NCCP, 16 (20.8%) were classified into the GERD-related NCCP group and 61 (79.2%) into the non-GERD-related NCCP group. BI (median, interquartile range) of the non-GERD-related NCCP group was lower than the control group at the proximal esophagus (2507 Ω, 2156-3217 vs 3855 Ω, 3238-4182, P = 0.001) but was similar at the distal esophagus. The GERD-related NCCP group showed lower BI than the control group at both the distal and proximal esophagus (2024 Ω, 1619-2308 vs 3203 Ω, 2366-3774, P = 0.007 and 2272 Ω, 1896-2908 vs 3855 Ω, 3238-4182, P = 0.003, respectively). At the distal esophagus, BI was lower in the GERD-related NCCP group than the non-GERD-related NCCP group (P = 0.002), whereas it did not differ between the 2 groups at the proximal esophagus. In conclusion, the mucosal integrity is impaired at the proximal esophagus in patients with non-GERD-related NCCP, which might be the pathogenic mechanism of NCCP.
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Affiliation(s)
- Yang Won Min
- From the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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30
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Ates F, Yuksel ES, Higginbotham T, Slaughter JC, Mabary J, Kavitt RT, Garrett CG, Francis D, Vaezi MF. Mucosal impedance discriminates GERD from non-GERD conditions. Gastroenterology 2015; 148:334-43. [PMID: 25448923 DOI: 10.1053/j.gastro.2014.10.010] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 10/09/2014] [Accepted: 10/14/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Current diagnostic tests for gastroesophageal reflux disease (GERD) are suboptimal and do not accurately and reliably measure chronicity of reflux. A minimally invasive device has been developed to assess esophageal mucosal impedance (MI) as a marker of chronic reflux. We performed a prospective longitudinal study to investigate MI patterns in patients with GERD and common nonreflux conditions, to assess MI patterns before and after treatment with proton pump inhibitors and to compare the performance of MI and wireless pH tests. METHODS We evaluated MI in 61 patients with erosive esophagitis, 81 with nonerosive but pH-abnormal GERD, 93 without GERD, 18 with achalasia, and 15 with eosinophilic esophagitis. MI was measured at the site of esophagitis and at 2, 5, and 10 cm above the squamocolumnar junction in all participants. MI was measured before and after acid suppressive therapy, and findings were compared with those from wireless pH monitoring. RESULTS MI values were significantly lower in patients with GERD (erosive esophagitis or nonerosive but pH-abnormal GERD) or eosinophilic esophagitis than in patients without GERD or patients with achalasia (P < .001). The pattern of MI in patients with GERD differed from that in patients without GERD or patients with eosinophilic esophagitis; patients with GERD had low MI closer to the squamocolumnar junction, and values increased axially along the esophagus. These patterns normalized with acid suppressive therapy. MI patterns identified patients with esophagitis with higher levels of specificity (95%) and positive predictive values (96%) than wireless pH monitoring (64% and 40%, respectively). CONCLUSIONS Based on a prospective study using a prototype device, measurements of MI detect GERD with higher levels of specificity and positive predictive values than wireless pH monitoring. Clinical Trials.gov, Number: NCT01556919.
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Affiliation(s)
- Fehmi Ates
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt Medical Center, Nashville, Tennessee
| | - Elif Saritas Yuksel
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt Medical Center, Nashville, Tennessee
| | - Tina Higginbotham
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt Medical Center, Nashville, Tennessee
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt Medical Center, Nashville, Tennessee
| | | | - Robert T Kavitt
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt Medical Center, Nashville, Tennessee
| | - C Gaelyn Garrett
- Vanderbilt Voice Center, Vanderbilt Institute for Medicine & Public Health, Nashville, Tennessee
| | - David Francis
- Vanderbilt Voice Center, Vanderbilt Institute for Medicine & Public Health, Nashville, Tennessee; Center for Surgical Quality and Outcomes Research, Vanderbilt Institute for Medicine & Public Health, Nashville, Tennessee
| | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt Medical Center, Nashville, Tennessee.
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31
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The development and treatment of periprosthetic leakage after prosthetic voice restoration. A literature review and personal experience part I: the development of periprosthetic leakage. Eur Arch Otorhinolaryngol 2014; 272:641-59. [PMID: 25404116 DOI: 10.1007/s00405-014-3394-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 11/07/2014] [Indexed: 01/04/2023]
Abstract
In the past 30 years, the use of a voice prosthesis has become the treatment of choice for the restoration of speech following laryngectomy. Not only is the placement of a voice prosthesis a simple surgical procedure, but it is also associated with a low rate of complications and an excellent success rate. Approximately, 20-30 % of all patients with voice prostheses, however, develop periprosthetic leakage with aspiration over time. Periprosthetic leakage is usually caused by an enlargement of the tracheo-oesophageal fistula and substantially affects the quality of life of the patients concerned. In a retrospective analysis of our patients, the incidence of periprosthetic leakage was 35.7 % in a total of 232 patients who underwent laryngectomy during a period of 20 years. Substantial enlargement of the tracheo-oesophageal fistula which required multiple treatments occurred in 12.5 % of the patients. In this review, the various causes of fistula enlargement are discussed on the basis of the literature and the experience that we have accumulated during the past 20 years in the management of patients with voice prostheses.
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32
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Felder M, Stucki AO, Stucki JD, Geiser T, Guenat OT. The potential of microfluidic lung epithelial wounding: towards in vivo-like alveolar microinjuries. Integr Biol (Camb) 2014; 6:1132-40. [PMID: 25205504 DOI: 10.1039/c4ib00149d] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) remains a major clinical challenge to date. Repeated alveolar epithelial microinjuries are considered as the starting point and the key event in both the development and the progression of IPF. Various pro-fibrotic agents have been identified and shown to cause alveolar damage. In IPF, however, no leading cause of alveolar epithelial microinjuries can be identified and the exact etiology remains elusive. New results from epidemiologic studies suggest a causal relation between IPF and frequent episodes of gastric refluxes resulting in gastric microaspirations into the lung. The effect of gastric contents on the alveolar epithelium has not been investigated in detail. Here, we present a microfluidic lung epithelial wounding system that allows for the selective exposure of alveolar epithelial cells to gastric contents. The system is revealed to be robust and highly reproducible. The thereby created epithelial microwounds are of tiny dimensions and best possibly reproduce alveolar damage in the lung. We further demonstrate that exposure to gastric contents, namely hydrochloric acid (HCl) and pepsin, directly damages the alveolar epithelium. Together, this novel in vitro wounding system allows for the creation of in vivo-like alveolar microinjuries with the potential to study lung injury and alveolar wound repair in vitro.
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Affiliation(s)
- M Felder
- ARTORG Center Lung Regeneration Technologies Lab, University of Bern, Murtenstrasse 50, 3010 Bern, Switzerland.
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Comparison of light and electron microscopy in measurement of esophageal intercellular space in children. J Pediatr Gastroenterol Nutr 2014; 59:232-6. [PMID: 24647333 DOI: 10.1097/mpg.0000000000000373] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVES A good objective marker of esophageal mucosal damage from gastroesophageal reflux disease (GERD) is lacking in children. Increased esophageal epithelial intercellular (EEIC) space measured using electron microscopy (EM) has been proposed as a surrogate of esophageal mucosal damage in adults with GERD. The aim of the present study was to compare EEIC space measured using EM and light microscopy (LM) in children with nonerosive reflux disease (NERD) with asymptomatic controls. METHODS Distal esophageal mucosal biopsy was used to measure EEIC space using EM in 35 NERD subjects and 8 controls. In a subset of these patients we used phase contrast LM to measure EEIC space area (26 NERD subjects and 8 controls). RESULTS The median (range) EEIC space measured using EM in the NERD group was 1.15 (0.74-1.64) μm compared with 0.93 (0.67-1.11) μm in the control group (P = 0.002). The median (range) EEIC space measured using LM was 14.4% (9.6%-26.3%) in the NERD group and 9.6% (8.5%-17.2%) in controls (P = 0.003). Using a cutoff value of 1.02 μm for normal EEIC space measured by EM, we obtained 73% sensitivity and 75% specificity to distinguish the NERD group from the control group, and using a cutoff value of 11.1% for EEIC space measured by LM, we obtained 96% sensitivity and 75% specificity. CONCLUSIONS EEIC space is increased in children with NERD compared with that in controls, suggesting that changes in EEIC space can be a useful marker of esophageal mucosal injury in children with NERD. Our results suggest that the accuracy of EM and LM to evaluate EEIC space changes in NERD is comparable, and LM may be a more cost-effective option.
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Xu T, Zhang XQ, Zou XP. Mechanisms of esophageal epithelial injury in gastroesophageal reflux disease. Shijie Huaren Xiaohua Zazhi 2014; 22:3030-3035. [DOI: 10.11569/wcjd.v22.i21.3030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) is a disease frequently encountered in gastroenterology department. Domestic scholars paid much attention on the anatomical basis of reflux when trying to describe the mechanisms of GERD, such as the decrease of tension of the lower esophageal sphincter (LES) and a transient lower esophageal sphincter (tLESR) and diaphragmatic hernia, and neglected the pathophysiological mechanisms of esophageal epithelial histological changes including cell necrosis, dilated intercellular space (DIS), and infiltration of inflammatory cells which were induced by the reflux contents including gastric acid, pepsin and bile. In this paper, we will elaborate the mechanisms of esophageal epithelia injury induced by common reflux contents at the cellular and molecular levels, focusing on the introduction and analysis of immune injury mechanism.
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Manivasagan P, Venkatesan J, Sivakumar K, Kim SK. Actinobacterial enzyme inhibitors--a review. Crit Rev Microbiol 2014; 41:261-72. [PMID: 24495095 DOI: 10.3109/1040841x.2013.837425] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Actinobacteria have potential as important new sources of enzyme inhibitors. Enzyme inhibitors have great demand in medicine, agriculture and biotechnology. In medicine, enzyme inhibitors can be used as therapeutic agents for bacterial, fungal, viral and parasitic diseases as well as treating cancer, neurodegenerative, immunological and cardiovascular diseases. Enzyme inhibitors are also valuable for the control of carbohydrate-dependent diseases such as diabetes, obesity and hyperlipidemia and melanogenesis in skin. They can be also involved in crop protection against plant pathogens, herbivorous pests and abiotic stresses such as drought. In this review, we discuss about several actinobacterial enzyme inhibitors with various industrial uses and biotechnological applications.
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Affiliation(s)
- Panchanathan Manivasagan
- Department of Chemistry, Marine Bioprocess Research Center, Pukyong National University , Busan , Republic of Korea and
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36
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Zhang S, Liu Z, Heldsinger A, Owyang C, Yu S. Intraluminal acid activates esophageal nodose C fibers after mast cell activation. Am J Physiol Gastrointest Liver Physiol 2014; 306:G200-7. [PMID: 24264049 PMCID: PMC3920110 DOI: 10.1152/ajpgi.00142.2013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Acid reflux in the esophagus can induce esophageal painful sensations such as heartburn and noncardiac chest pain. The mechanisms underlying acid-induced esophageal nociception are not clearly understood. In our previous studies, we characterized esophageal vagal nociceptive afferents and defined their responses to noxious mechanical and chemical stimulation. In the present study, we aim to determine their responses to intraluminal acid infusion. Extracellular single-unit recordings were performed in nodose ganglion neurons with intact nerve endings in the esophagus using ex vivo esophageal-vagal preparations. Action potentials evoked by esophageal intraluminal acid perfusion were compared in naive and ovalbumin (OVA)-challenged animals, followed by measurements of transepithelial electrical resistance (TEER) and the expression of tight junction proteins (zona occludens-1 and occludin). In naive guinea pigs, intraluminal infusion with either acid (pH = 2-3) or capsaicin did not evoke an action potential discharge in esophageal nodose C fibers. In OVA-sensitized animals, following esophageal mast cell activation by in vivo OVA inhalation, intraluminal acid infusion for about 20 min started to evoke action potential discharges. This effect is further confirmed by selective mast cell activation using in vitro tissue OVA challenge in esophageal-vagal preparations. OVA inhalation leads to decreased TEER and zona occludens-1 expression, suggesting an impaired esophageal epithelial barrier function after mast cell activation. These data for the first time provide direct evidence of intraluminal acid-induced activation of esophageal nociceptive C fibers and suggest that mast cell activation may make esophageal epithelium more permeable to acid, which subsequently may increase esophageal vagal nociceptive C fiber activation.
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Affiliation(s)
- Shizhong Zhang
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Zhenyu Liu
- 2Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Andrea Heldsinger
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Chung Owyang
- 1Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan Medical School, Ann Arbor, Michigan; and
| | - Shaoyong Yu
- 2Johns Hopkins University School of Medicine, Baltimore, Maryland
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Hall M, Wenner J, Öberg S. The postprandial acid pocket does not extend into most distal esophagus: evidence from pH studies performed immediately above the squamocolumnar junction. Scand J Gastroenterol 2014; 49:15-22. [PMID: 24256116 DOI: 10.3109/00365521.2013.845797] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The postprandial acid pocket is suggested to be an important factor in the pathogenesis of gastroesophageal reflux disease (GERD) as it according to the theory extends into the distal esophagus. The aim of this study was to test the hypothesis that the acid pocket transverses the squamocolumnar junction (SCJ) and exposes the most distal esophagus to gastric acid for extended periods following a meal. MATERIAL AND METHODS Fifty asymptomatic volunteers and 75 patients with GERD underwent 48-h pH monitoring with the electrode of a pH capsule placed immediately above the SCJ. The characteristics of esophageal acid exposure from the 90-min postprandial periods were compared with those observed during the upright, preprandial periods. RESULTS In asymptomatic controls, the degree of postprandial esophageal acid exposure was similar to that observed in the preprandial periods (median % time with pH <4, 2.2 vs. 2.6, p = 0.165). In contrast, symptomatic patients had significantly greater acid exposure in the postprandial compared with the preprandial periods (median % time with pH <4, 15.5 vs. 8.5, p < 0.001). The higher degree of acid exposure during the postprandial periods was due to a significantly higher number of short reflux episodes and reflux events with long durations were infrequent. CONCLUSION Postprandial acid exposure in the most distal esophagus was characterized by numerous short reflux events, and reflux events of long durations were rare. Our observations suggest that the acid pocket is confined to the stomach, questioning the importance of the acid pocket in GERD.
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Affiliation(s)
- Mats Hall
- Department of Gastroenterology, Skåne University Hospital, Clinical Sciences Lund, Lund University
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Farré R. Pathophysiology of gastro-esophageal reflux disease: a role for mucosa integrity? Neurogastroenterol Motil 2013; 25:783-99. [PMID: 23937353 DOI: 10.1111/nmo.12201] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 07/16/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastro-esophageal reflux disease (GERD) is very prevalent and has a high burden on health security system costs. Nevertheless, pathophysiology is complex and not well-understood. Several mechanisms have been proposed: decreased salivation, impaired esophageal clearance, decreased lower esophageal sphincter pressure resting tone, presence of hiatal hernia, increased number of transient lower esophageal sphincter relaxations (TLESRs), increased acid, and pepsin secretion, pyloric incompetence provoking duodeno-gastro-esophageal reflux of bile acids and trypsin. Independent of the relevance of each mechanism, the ultimate phenomenon is that mucosal epithelium is exposed for a longer time to agents as acid and pepsin or is in contact to luminal agents not commonly present in gastric refluxate as trypsin or bile acids. This leads to a visible damage of the epithelium (erosive esophagitis -EE) or impairing mucosal integrity without any sign of macroscopic alteration as occurs in non-erosive reflux disease (NERD). Luminal factors are not the only responsible for such impairment; more recent data indicate that endogenous factors may also play a role. PURPOSE This review will update the most recent findings on the putative pathophysiological mechanisms and specially will focus on the role of esophageal mucosal integrity in GERD. Methodologies used for the evaluation of mucosal integrity, its relevance in EE and NERD, its involvement in symptoms perception and the effect of luminal and endogenous factors will be discussed.
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Affiliation(s)
- R Farré
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos II, Madrid, Spain
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Weijenborg PW, Bredenoord AJ. How reflux causes symptoms: reflux perception in gastroesophageal reflux disease. Best Pract Res Clin Gastroenterol 2013; 27:353-64. [PMID: 23998974 DOI: 10.1016/j.bpg.2013.06.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 06/11/2013] [Accepted: 06/23/2013] [Indexed: 02/07/2023]
Abstract
In gastroesophageal reflux disease (GERD) symptoms arise due to reflux of gastric content into the oesophagus. However, the relation between magnitude and onset of reflux and symptom generation in GERD patients is far from simple; gastroesophageal reflux occurs several times a day in everyone and the majority of reflux episodes remains asymptomatic. This review aims to address the question how reflux causes symptoms, focussing on factors leading to enhanced reflux perception. We will highlight esophageal sensitivity variance between subtypes of GERD, which is influenced by peripheral sensitization of primary afferents, central sensitization of spinal dorsal horn neurons, impaired mucosal barrier function and genetic factors. We will also discuss the contribution of specific refluxate characteristics to reflux perception, including acidity, and the role of bile, pepsin and gas and proximal extent. Further understanding of reflux perception might improve GERD treatment, especially in current partial responders to therapy.
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Affiliation(s)
- Pim W Weijenborg
- Dept. of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Meibergdreef 9, Postbus 22660, 1100 DD Amsterdam, The Netherlands.
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Slow-tight binding inhibition of pepsin by an aspartic protease inhibitor from Streptomyces sp. MBR04. Int J Biol Macromol 2012; 51:165-74. [PMID: 22522047 DOI: 10.1016/j.ijbiomac.2012.04.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 04/03/2012] [Accepted: 04/04/2012] [Indexed: 11/20/2022]
Abstract
The present article reports a low molecular weight aspartic protease inhibitor from a Streptomyces sp. MBR04 exhibiting a two-step inhibition mechanism against pepsin. The kinetic interactions revealed a reversible, competitive, slow-tight binding inhibition with an IC(50) and K(i) values of 4.5 nM and 4 nM respectively. The conformational changes induced upon inhibitor binding to pepsin was monitored by far and near UV analysis, demonstrated that the inhibitor binds to the active site and causes inactivation. Chemical modification of the inhibitor with WRK and TNBS abolished the antiproteolytic activity of the inhibitor.
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Probiotic encapsulation technology: from microencapsulation to release into the gut. Pharmaceutics 2012; 4:149-63. [PMID: 24300185 PMCID: PMC3834910 DOI: 10.3390/pharmaceutics4010149] [Citation(s) in RCA: 108] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Revised: 01/20/2012] [Accepted: 01/31/2012] [Indexed: 12/02/2022] Open
Abstract
Probiotic encapsulation technology (PET) has the potential to protect microorgansisms and to deliver them into the gut. Because of the promising preclinical and clinical results, probiotics have been incorporated into a range of products. However, there are still many challenges to overcome with respect to the microencapsulation process and the conditions prevailing in the gut. This paper reviews the methodological approach of probiotics encapsulation including biomaterials selection, choice of appropriate technology, in vitro release studies of encapsulated probiotics, and highlights the challenges to be overcome in this area.
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Abstract
Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.
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Lundin P, Karpefors M, Carlsson K, Hansen MB, Ruth M. Bioimpedance spectroscopy: a new tool to assess early esophageal changes linked to gastroesophageal reflux disease? Dis Esophagus 2011; 24:462-9. [PMID: 21385284 DOI: 10.1111/j.1442-2050.2011.01181.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Bioimpedance spectroscopy can identify pathological changes related to precancerous lesions of the cervix uteri and esophagus. It therefore has the potential to detect early reflux-related changes in the esophageal mucosa, such as dilated intercellular spaces. The reliable detection of dilated intercellular spaces at the time of endoscopy would yield a significant diagnostic advantage for separating patients with functional heartburn from the large proportion of patients with gastroesophageal reflux symptoms but no macroscopic esophagitis or pathological acid exposure. The bioimpedance of the esophageal mucosa, measured with a small caliber probe, was evaluated in a series of preclinical experiments. First, sections of rabbit esophageal epithelium were mounted in Ussing chambers and exposed to solutions at pH 7.4 or pH 1.5 for 45 minutes. Impedance measurements were taken at varying probe pressures. Second, rabbit esophageal epithelia were perfused for 45 minutes in situ with pH 1.1 or control solutions and impedance measurements taken. Samples from both in vitro and in situ experiments were taken for morphological examination by light microscopy. Finally, esophageal bioimpedance was measured in awake dogs with permanent esophagocutaneous stoma. The in situ experiments demonstrated that morphological changes in the esophageal mucosa could be discerned by the use of bioimpedance spectroscopy. The variability in resistivity was species-independent but was affected by the pressure applied to the probe. The results suggest that evaluation of bioimpedance spectroscopy for use in a clinical setting is warranted. Small morphological differences in the esophageal mucosa may be detected by the use of bioimpedance spectroscopy.
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Affiliation(s)
- P Lundin
- AstraZeneca Research & Development, Early Clinical Development, Mölndal, Sweden.
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Bathoorn E, Daly P, Gaiser B, Sternad K, Poland C, Macnee W, Drost EM. Cytotoxicity and induction of inflammation by pepsin in Acid in bronchial epithelial cells. Int J Inflam 2011; 2011:569416. [PMID: 21785693 PMCID: PMC3139191 DOI: 10.4061/2011/569416] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 05/17/2011] [Accepted: 05/20/2011] [Indexed: 11/20/2022] Open
Abstract
Introduction. Gastroesophageal reflux has been associated with chronic inflammatory diseases and may be a cause of airway remodelling. Aspiration of gastric fluids may cause damage to airway epithelial cells, not only because acidity is toxic to bronchial epithelial cells, but also since it contains digestive enzymes, such as pepsin. Aim. To study whether pepsin enhances cytotoxicity and inflammation in airway epithelial cells, and whether this is pH-dependent. Methods. Human bronchial epithelial cells were exposed to increasing pepsin concentrations in varying acidic milieus, and cell proliferation and cytokine release were assessed. Results. Cell survival was decreased by pepsin exposure depending on its concentration (F = 17.4) and pH level of the medium (F = 6.5) (both P < 0.01). Pepsin-induced interleukin-8 release was greater at lower pH (F = 5.1; P < 0.01). Interleukin-6 induction by pepsin was greater at pH 1.5 compared to pH 2.5 (mean difference 434%; P = 0.03). Conclusion. Pepsin is cytotoxic to bronchial epithelial cells and induces inflammation in addition to acid alone, dependent on the level of acidity. Future studies should assess whether chronic aspiration causes airway remodelling in chronic inflammatory lung diseases.
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Affiliation(s)
- Erik Bathoorn
- ELEGI, Colt Research Laboratories, MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH 16 4TJ, UK
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Park SY, Sohn UD. Inhibitory effect of rosiglitazone on the acid-induced intracellular generation of hydrogen peroxide in cultured feline esophageal epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 2011; 383:191-201. [PMID: 21212935 DOI: 10.1007/s00210-010-0594-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2010] [Accepted: 12/19/2010] [Indexed: 01/28/2023]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARγ) agonists have been reported to enhance antioxidant defenses by increasing levels of catalase and copper-zinc superoxide dismutase (Cu/Zn SOD) in oligodendrocyte progenitor cells. In this study, we investigated the effects of the PPARγ agonist, rosiglitazone, on hydrogen peroxide (H(2)O(2)) generation by acidified medium at pH 5.5 (AM5.5), which is in the pH range of duodenogastric refluxates, in primary cultured feline esophageal epithelial cells (EEC). Successful isolation of EEC was identified by immunocytochemistry. AM5.5- and rosiglitazone-induced cell viabilities were determined using 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assays. The NAD(P)H oxidase activity was measured, and expression of catalase or SOD protein by AM5.5 in the absence and presence of rosiglitazone was assessed using western blotting analysis. PPARγ protein and mRNA were constitutively expressed in EEC. In the incubation with rosiglitazone alone, cell viability was shown more than 90% at 0-10 μM for 72 h. After exposure to AM5.5 for 8 h, intracellular H(2)O(2) was significantly generated. Treatment with rosiglitazone prior to and during exposure to AM5.5 inhibited the H(2)O(2) generation whereas the specific PPARγ antagonist GW9662 offsets the inhibitory action of rosiglitazone. H(2)O(2) generation was also prevented by a nonspecific ROS scavenger N-acetylcysteine or an inhibitor of NADPH oxidase diphenyleneiodonium. The enhanced AM5.5-induced NAD(P)H oxidase activity was not suppressed by rosiglitazone. Instead, the pretreatment of rosiglitazone enhanced the protein expression of catalase, Cu/Zn SOD, and Mn SOD, which are endogenous antioxidative enzymes. These findings indicate that rosiglitazone inhibits AM5.5-induced intracellular H(2)O(2) production, which occurs via NAD(P)H oxidase activation, by using a PPARγ-dependent pathway, and that the underlying mechanism involves an increase in the expression of catalase and SOD proteins.
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Affiliation(s)
- Sun Young Park
- Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea
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Orlando RC. The integrity of the esophageal mucosa. Balance between offensive and defensive mechanisms. Best Pract Res Clin Gastroenterol 2010; 24:873-82. [PMID: 21126700 PMCID: PMC2995989 DOI: 10.1016/j.bpg.2010.08.008] [Citation(s) in RCA: 105] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 08/17/2010] [Accepted: 08/23/2010] [Indexed: 01/31/2023]
Abstract
Heartburn is the most common and characteristic symptom of gastroesophageal reflux disease. It ultimately results from contact of refluxed gastric acid with nociceptors within the esophageal mucosa and transmission of this peripheral signal to the central nervous system for cognition. Healthy esophageal epithelium provides an effective barrier between refluxed gastric acid and esophageal nociceptors; but this barrier is vulnerable to attack and damage, particularly by acidic gastric contents. How gastric acid is countered by defensive elements within the esophageal mucosa is a major focus of this discussion. When the defense is successful, the subject is asymptomatic and when unsuccessful, the subject experiences heartburn. Those with heartburn commonly fall into one of three endoscopic types: nonerosive reflux disease, erosive esophagitis and Barrett's esophagus. Although what determines endoscopic type remains unknown; it is proposed herein that inflammation plays a key, modulating role.
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Affiliation(s)
- Roy C Orlando
- University of North Carolina at Chapel Hill, 27599, USA.
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Abstract
Proton pump inhibitors (PPIs) are extremely effective for mucosal healing of reflux esophagitis, but less so for relieving the symptom of heartburn. PPIs block the secretion of gastric acid, the caustic effects of which have been assumed to be the primary culprit in the pathogenesis of reflux esophagitis. However, mounting data suggest that reflux-stimulated, immune-mediated mechanisms may underlie the development of esophagitis in patients with gastroesophageal reflux disease (GERD). Thus, the future of GERD therapy, particularly for patients who are refractory to PPIs, may be the targeting of proteins such as proteinase-activated receptor-2, which have central roles in the generation of immune-mediated esophageal mucosal damage and in eliciting the symptom of heartburn.
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Abstract
OBJECTIVES/HYPOTHESIS The vocal fold epithelium provides a barrier to the entry of inhaled and systemic challenges. However, the location of the epithelium makes it vulnerable to damage. Past research suggests, but does not directly demonstrate, that exposure to gastric reflux adversely affects the function of the epithelial barrier. Understanding the nature of reflux-induced epithelial barrier dysfunction is necessary to better recognize the mechanisms for vocal fold susceptibility to this disease. Therefore, we examined the effects of physiologically relevant reflux challenges on vocal fold transepithelial resistance and gross epithelial and subepithelial appearance. STUDY DESIGN Ex vivo, mixed design with between-group and repeated-measures analyses. METHODS Healthy, native porcine vocal folds (N = 52) were exposed to physiologically relevant acidic pepsin, acid-only, or pepsin-only challenges and examined with electrophysiology and light microscopy. For all challenges, vocal folds exposed to a neutral pH served as control. RESULTS Acidic pepsin and acid-only challenges, but not pepsin-only or control challenges significantly reduced transepithelial resistance within 30 minutes. Reductions in transepithelial resistance were irreversible. Challenge exposure produced minimal gross changes in vocal fold epithelial or subepithelial appearance as evidenced by light microscopy. CONCLUSIONS These findings demonstrate that acidic environments characteristic of gastric reflux compromise epithelial barrier function without gross structural changes. In healthy, native vocal folds, reductions in transepithelial resistance could reflect reflux-related epithelial disruption. These results might guide the development of pharmacologic and therapeutic recommendations for patients with reflux, such as continued acid-suppression therapy and patient antireflux behavioral education.
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Affiliation(s)
- Elizabeth Erickson
- Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, USA
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Abstract
The precise mechanisms whereby gastro-oesophageal reflux disease causes reflux oesophagitis and Barrett's oesophagus are not clear, even though these diseases have been known to be linked for many years. Recent studies indicate a role for the reflux-induced inflammatory response of oesophageal squamous epithelial cells and the immune cells in the pathogenesis of reflux oesophagitis. Although reflux oesophagitis commonly heals with oesophageal squamous cell regeneration, in some individuals the oesophagus heals through the process of metaplasia, a condition termed Barrett's oesophagus. Recent studies indicate that individual differences in the reflux-mediated response of oesophageal squamous epithelial cells in the type of immune response and/or in signalling pathways that regulate cell proliferation or cell phenotype may determine whether the oesophagus heals with the regeneration of squamous cells or through Barrett's metaplasia.
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Affiliation(s)
- Rhonda F Souza
- Department of Medicine, VA North Texas Health Care System, 4500 South Lancaster Road, Dallas, TX 75216, USA.
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Ito H, Iijima K, Ara N, Asanuma K, Endo H, Asano N, Koike T, Abe Y, Imatani A, Shimosegawa T. Reactive nitrogen oxide species induce dilatation of the intercellular space of rat esophagus. Scand J Gastroenterol 2010; 45:282-291. [PMID: 20001645 DOI: 10.3109/00365520903469956] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Dilatation of the intercellular space (DIS) of the esophageal epithelium is recognized as one of the earliest histological changes in gastroesophageal reflux disease patients. At the human gastroesophageal junction, reactive nitrogen oxide species (RNOS) are generated luminally through the entero-salivary re-circulation of dietary nitrate. In cases with gastroesophageal reflux, the site of luminal RNOS generation may shift to the distal esophagus. The aim of this study was to investigate whether luminal RNOS exposure could be involved in the pathogenesis of DIS. MATERIAL AND METHODS Rat esophageal mucosa was studied with an Ussing chamber model. On the luminal side of the chamber, RNOS were generated by the acidification of physiologic concentrations of sodium nitrite (1.0 or 5.0 mM). Esophageal barrier function was assessed by means of electrophysiological transmembrane resistance and membrane permeability by means of (3)H-mannitol flux. The dimensions of the intercellular spaces were assessed by using transmission electron microscopy. RESULTS Administration of acid plus sodium nitrite induced DIS of the esophageal epithelium, and this ultrastructural morphological change was accompanied by a concomitant decrease in the transmembrane resistance and an increase in the epithelial permeability. The DIS induced by luminal RNOS was also confirmed in an in vivo exposure model. CONCLUSIONS The present animal study indicates that the RNOS generated by the acidification of salivary nitrite in the presence of refluxed gastric acid in the esophagus could be a luminal factor that is responsible for the induction of DIS. Further studies are warranted to investigate the clinical relevance of the present findings to the human situation.
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Affiliation(s)
- H Ito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan
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