Exploring the clinical relevance of "Angico Gum": an effective biopolymer for topical protection of oesophageal mucosa in gastroesophageal reflux disease patients.

OBJECTIVES: Angico gum (AG) (Anadenanthera colubrina var. Cebil [Griseb.] Altschul) is utilized by some Brazilian communities to alleviate symptoms from gastroesophageal reflux disease. Here, we aimed to investigate the "in vitro" topical protective capacity of AG on human esophageal mucosa. METHODS: Biopsies of the distal esophageal mucosa were collected from 35 patients with heartburn (24 non-erosive and 11 with erosive oesophagitis (EE)) and mounted in Üssing chambers. AG was applied topically, followed by exposure with acid solution (pH 2.0 or pH 1.0), where transepithelial electrical resistance (TER) and The transepithelial permeability for fluorescein was assessed. The incubation of the AG labeled with FITC in the esophageal mucosa was localized by fluorescence microscopy. KEY FINDINGS: Pretreatment with AG prevented the drop in TER induced by acid solution, as well as significantly decreases the fluorescein permeability in non-erosive patients. The protective effect of AG was sustained for up to 120 min both in biopsies of non-erosive and erosive esophagitis. Confocal microscope images showed mucosal luminal adherence of FITC-labeled AG. CONCLUSION: AG had a prolonged topical protective effect against acid solution in mucosal biopsies of patients with non-erosive and erosive esophagitis.

Pathophysiology of gastro-oesophageal reflux disease: implications for diagnosis and management.

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.

Pepsin Inhibitors Prevent Inflammation and Loss of Laryngeal Barrier Function in Mice with Gastroesophageal Reflux.

OBJECTIVE: This study aimed to evaluate the role of pepsin inhibitors in the inflammatory response and their effects on laryngeal mucosal integrity during gastroesophageal reflux (GERD) under in vivo conditions. METHODS: A surgical model of GERD was used, in which mice were treated with pepstatin (0.3 mg/kg) or darunavir (8.6 mg/kg) for 3 days. On the third day after the experimental protocol, the laryngeal samples were collected to assess the severity of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and paracellular epithelial permeability to fluorescein). RESULTS: The surgical GERD model was reproduced. It showed features of inflammation and loss of barrier function in the laryngeal mucosa. Pepstatin and darunavir administration suppressed laryngeal inflammation and preserved laryngeal mucosal integrity. CONCLUSION: Pepsin inhibition by the administration of pepstatin and darunavir improved inflammation and protected the laryngeal mucosa in a mouse experimental model of GERD. LEVEL OF EVIDENCE: NA Laryngoscope, 134:3080-3085, 2024.

Laryngeal and Esophageal Mucosal Protection Using the Angico Gum Biopolymer in a Mouse Model of Reflux.

OBJECTIVE: This study aimed to evaluate the in vivo protective effect of the angico gum biopolymer in reducing the inflammatory response and preserving the integrity of the laryngeal and esophageal mucosa. STUDY DESIGN: Animal study. METHODS: A murine surgical model of gastroesophageal reflux disease was accomplished and subsequently treated with angico gum or omeprazole. On days 3 and 7 post surgery, samples of the larynx and esophagus, respectively, were collected to measure the level of inflammation (wet weight and myeloperoxidase activity) and mucosal integrity (transepithelial electrical resistance and mucosal permeability to fluorescein). RESULTS: Angico gum and omeprazole decreased laryngeal inflammation (wet weight and myeloperoxidase activity) and dramatically improved the integrity of the laryngeal mucosa. It also reduced inflammation (decreased wet weight and myeloperoxidase activity) of the esophagus and preserved the barrier function (inferred by assessing the integrity of the mucosa). CONCLUSION: This study demonstrates the protective effect of angico gum in an experimental gastroesophageal reflux disease model. Angico gum attenuates inflammation and impairment of the mucosal barrier function not only in the larynx but also in the esophagus. LEVEL OF EVIDENCE: NA Laryngoscope, 133:162-168, 2023.

Laryngeal Mucosa Alterations in Mice Model of Gastroesophageal Reflux: Effects of Topical Protection.

OBJECTIVES/HYPOTHESIS: The objectives of this study were to evaluate laryngeal inflammation and mucosal integrity in a murine model of reflux disease and to assess the protective effects of topical agents including alginate, hyaluronic acid, and cashew gum. STUDY DESIGN: Animal study. METHODS: A surgical murine model of reflux disease was evaluated at 3 or 7 days postsurgery, and laryngeal samples were collected to measure inflammation (wet weight and myeloperoxidase [MPO]) and mucosal integrity (transepithelial resistance [TER] and mucosal permeability to fluorescein). Additional groups of animals were administered one of several topical agents (alginate, hyaluronic acid, or cashew gum) daily, and laryngeal inflammation and mucosal integrity were evaluated at 3 days postsurgery. RESULTS: At 3 days, and not 7 days postsurgery, we observed increased laryngeal wet weight and MPO, decreased laryngeal TER, and increased laryngeal mucosa permeability. Alginate partially decreased laryngeal inflammation (wet weight and not MPO) and dramatically improved laryngeal mucosal integrity. Conversely, hyaluronic acid eliminated the inflammation; however, it had no effect on laryngeal mucosal integrity impairment. Cashew gum eliminated laryngeal inflammation as well as the impairment in laryngeal mucosal integrity. CONCLUSIONS: This study shows that a surgical model of reflux disease induced laryngeal inflammation and impairment in laryngeal barrier function. These observed alterations were partially attenuated by alginate and hyaluronic acid and completely reversed by cashew gum. LEVEL OF EVIDENCE: NA Laryngoscope, 2020.

Polysaccharide from Gracilaria caudata protects the human esophageal mucosal barrier: A differential topical effect and structural dependence.

This study aimed to evaluate the in vitro protective effect of topical treatment with a native sulfated polysaccharide of G. caudata (SP-Gc), hydrolyzed (H-SP-Gc), or desulfated (D-SP-Gc) polysaccharide of Gracilaria caudata in esophageal biopsies obtained from GERD patients. Biopsies were obtained from nonerosive reflux disease (NERD) patients and from erosive esophagitis patients. Then, the biopsies were mounted in an Ussing chamber to measure the basal transepithelial electrical resistance (TEER). The effect of mucosal exposure to an acid solution on TEER was analyzed with or without different concentrations (1, 0.3 or 1%) of SP-Gc, H-SP-Gc, or D-SP-Gc, precoated on the mucosa. Basal esophageal mucosal electrical resistance was significantly lower in erosive esophagitis than from NERD. Mucosal samples precoated with native SP-Gc (1%) significantly prevented TEER drop induced by an acidic solution in NERD, but this effect was not observed in erosive esophagitis. Topical application of D-SP-Gc showed no difference compared to native SP-Gc. However, when treated with chemically-modified SP-Gc, the protective effect observed with native SP-Gc was lost. The present study indicated that SP-Gc protects the human esophageal mucosal barrier in NERD patients. This effect is dependent on the structure but is independent of the presence of sulfate.

Impairment of rat oesophageal muscle contractility associated with experimental non-erosive oesophageal mucosal damage.

NEW FINDINGS: What is the central question of this study? Is the responsiveness of isolated segments of the rat oesophagus to contractile or relaxant stimuli susceptible to acute luminal exposure of the oesophagus to an acid solution that contains pepsin and bile salt? What is the main finding and its importance? The study reveals that luminal acidity is an important factor that disrupts barrier function in the oesophagus to allow the diffusion of noxious agents, such as bile acid, that alter the contractile status of the oesophageal body, even in the absence of inflammation. ABSTRACT: We investigated whether the experimental simulation of duodenogastro-oesophageal reflux alters the contractile responsiveness of rat oesophageal strips. After 30 min of luminal exposure to a solution at acid pH that contained pepsin and taurodeoxycholic acid, isolated strips of the rat oesophagus and gastro-oesophageal junction were subjected to contractile or relaxing stimuli. Acid challenge decreased the responsiveness of oesophageal strips to contractile stimulation, especially in oesophageal preparations that were mounted following the circular orientation of the muscularis externa layer. The contractility of longitudinal preparations of the rat oesophagus appeared less susceptible to the deleterious effects of acid challenge. In contrast, the responsiveness of ring-like preparations from the gastro-oesophageal junction to contractile stimulation was unaltered by acid challenge. Taurodeoxycholic acid decreased the responsiveness of circular oesophageal preparations to KCl, an effect that was exacerbated by luminal acidity. On the contrary, although the relaxant ability of the rat oesophagus did not change, acid challenge increased the relaxant efficacy of sodium nitroprusside and isoprenaline in strips of the gastro-oesophageal junction. A significant decrease in transepithelial electrical resistance was seen when the oesophageal mucosa was challenged at pH 1 but not at pH 4. Treatment with alginate blunted the deleterious effects of acid challenge on transepithelial electrical resistance and the responsiveness of oesophageal preparations to KCl. The present findings support the notion that luminal acidity is an important factor that disrupts barrier function in the oesophagus to allow the diffusion of noxious agents, such as bile acid, that alter the contractile status of the oesophagus.

Topical protection of mice laryngeal mucosa using the natural product cashew gum.

OBJECTIVES/HYPOTHESIS: Evaluate the effect of in vitro exposure of mice laryngeal mucosa to solutions that simulated human gastric juice and to assess the topical protective effect of cashew gum on mice laryngeal mucosal integrity in vitro. STUDY DESIGN: Animal study. METHODS: Murine (Swiss) laryngeal samples were mounted in Ussing chambers. The luminal side of biopsies was exposed to solutions of different acidity with or without pepsin and/or taurodeoxycholic acid (TDC). Transepithelial electrical resistance (TER) was continuously recorded. The topical protective effect of cashew gum solution was evaluated by precoating the biopsies before the exposure with a solution at pH 5 containing 5 mM TDC. Changes in TER and mucosal permeability to fluorescein were measured. RESULTS: Exposure of laryngeal mucosa to acidic solutions containing pepsin and TDC provoked a pH-dependent drop in TER with the maximal effect at pH 1, but still present at pH 5 (weakly acidic). The exposure of the laryngeal mucosa to a solution of pH 5 with TDC, but not with pepsin, produced a dose-dependent decrease in TER. Precoating the mucosa with cashew gum prevented the reduction of TER and increased transepithelial permeability by exposure to a solution at pH5 containing TDC. CONCLUSIONS: Weakly acidic solutions containing bile acids can produce impairment of laryngeal epithelial barrier, which may be protected by topical treatment with cashew gum. LEVEL OF EVIDENCE: NA. Laryngoscope, 128:1157-1162, 2018.

A novel murine model of esophageal nonerosive reflux disease: from inflammation to impairment in mucosal integrity.

Nonerosive reflux disease (NERD) is a highly prevalent phenotype of the gastroesophageal reflux disease. In this study, we developed a novel murine model of NERD in mice with microscopic inflammation and impairment in the epithelial esophageal barrier. Female Swiss mice were subjected to the following surgical procedure: the transitional region between the forestomach and the glandular portion of the stomach was ligated, and a nontoxic ring was placed around the duodenum near the pylorus. The control group underwent sham surgery. The animals were euthanized at 1, 3, 7, and 14 days after surgery. Survival and body weight were monitored daily. Esophageal wet weight, macroscopic lesion, histopathological alterations, myeloperoxidase (MPO) activity, cytokine levels, transepithelial electrical resistance (TEER), and mucosal permeability were evaluated. The survival rate was 78% at 14 days, with mild loss in body weight. Surgery did not induce erosive esophagitis but instead induced microscopic inflammation and increased esophageal wet weight, IL-6, keratinocyte-derived cytokine (KC) levels, and MPO activity with maximal peak between 3 and 7 days and resolution at 14 days postsurgery. Epithelial esophageal barrier was evaluated in operated mice at 7 and 14 days postsurgery; a decrease in TEER and increase in the esophageal epithelial permeability were observed compared with the sham-operated group. In addition, the inhibition of acid secretion with omeprazole significantly prevented the esophageal inflammation and impairment of barrier function at 7 days postsurgery. Thus we established a novel experimental model of NERD in mice, which can contribute to understanding the pathophysiological events associated with NERD.NEW & NOTEWORTHY In this study, we standardized an experimental model of nonerosive reflux disease (NERD) in mice. This model involves an acute inflammatory response followed by impaired esophageal mucosal integrity, even in the absence of inflammation. Thus this model can serve for evaluation of pathophysiological aspects of NERD and open new perspectives for therapeutic strategies for patients with this disorder.

Estudo prospectivo comparativo de duas modalidades de posicionamento do sensor de phmetria esofágica prolongada: por manometria esofágica e pela viragem do Ph / Comparative prospective study of two positioning modes of 24-hour esophageal pH monitoring: by esophageal manometry and by the pH step-up technique

RACIONAL: Por padronização aceita internacionalmente, posiciona-se o sensor distal de pHmetria esofágica a 5 cm acima da borda superior do esfíncter inferior do esôfago, localizado por manometria esofágica. Porém, vários autores sugerem técnicas alternativas de posicionamento que prescindem da manometria. Dentre essas, destaca-se a da viragem do pH, tema este controverso pela sua duvidosa confiabilidade. OBJETIVO: Avaliar a adequação do posicionamento do sensor distal de pHmetria pela técnica de viragem do pH, considerando-se a presença, o tipo e o grau de erro de posicionamento que tal técnica proporciona, e também estudar a influência da posição adotada pelo paciente durante a técnica da viragem. MÉTODOS: Foram estudados de modo prospectivo, durante o período de 1 ano, 1.031 pacientes. Durante entrevista clínica, foram registrados os dados demográficos e as queixas clínicas apresentadas. Todos foram submetidos a manometria esofágica para localização do esfíncter inferior do esôfago e a técnica da viragem do pH. A identificação do ponto de viragem foi realizada de dois modos distintos, caracterizando dois grupos de estudo: com o paciente sentado (grupo I - 450 pacientes) e com o paciente em decúbito dorsal horizontal (grupo II - 581 pacientes). Após a identificação do ponto de viragem, o sensor distal de pHmetria era posicionado na posição padronizada, baseada na localização manométrica do esfíncter. Registrava-se onde seria posicionado o sensor de pH se fosse adotada a técnica da viragem. Para avaliação da adequação do posicionamento, considerou-se que o erro é representado pela diferença (em centímetros) entre a localização padronizada (manométrica) e a localização que seria adotada caso fosse empregada a técnica da viragem. Considerou-se que o erro seria grosseiro se fosse maior que 2 cm. Analisou-se também o tipo de erro mais freqüente (se acima ou abaixo da posição padronizada). Foram incluídos todos pacientes que aceitaram participar...

BACKGROUND: By internationally accepted standardization, the esophageal pH-meter distal sensor is positioned 5 cm above the superior border of the lower esophageal sphincter, identified by esophageal manometry. However, several authors suggest alternative positioning techniques that leave out the manometry; among such techniques, the pH step-up is the one to be pointed out. This subject is controversial; some publications state that the step-up technique is not reliable while some others consider it reliable. AIMS: Considering the existent controversy and the small number of prospective works with suitable sample and methodology, we have idealized the present study, that aims the evaluation of the suitability of the pH-meter distal sensor positioning based on the step-up technique, by analyzing the presence, the type and the degree of the error of positioning that such technique provides and the influence of the position adopted by the patient during the procedure. METHODS: One thousand and thirty one patients conducted to the esophageal pH-meter procedure were studied in a prospective way. During the clinical interview, the demographic data and the presented clinical complaints were registered. All the patients were submitted to both esophageal manometry in order to localize the lower esophageal sphincter and the pH step-up technique, that consists of the introduction of the pH-meter sensor in the gastric chamber and in the sensor's gradual traction until the pH steps up to levels over 4. The step-up point was identified by two distinct ways, characterizing two study groups: with the sitting patient (group I - 450 patients) and with the patient in supine position (group II - 581 patients). After the step-up point identification, the pH-meter distal sensor was placed in the standard position (based on the sphincter manometric placement). It was registered where the pH sensor would be positioned if the step-up technique were adopted. To...

[Comparative prospective study of two positioning modes of 24-hour esophageal pH monitoring: by esophageal manometry and by the pH step-up technique]. / Estudo prospectivo comparativo de duas modalidades de posicionamento do sensor de phmetria esofágica prolongada: por manometria esofágica e pela viragem do pH.

BACKGROUND: By internationally accepted standardization, the esophageal pH-meter distal sensor is positioned 5 cm above the superior border of the lower esophageal sphincter, identified by esophageal manometry. However, several authors suggest alternative positioning techniques that leave out the manometry; among such techniques, the pH step-up is the one to be pointed out. This subject is controversial; some publications state that the step-up technique is not reliable while some others consider it reliable. AIMS: Considering the existent controversy and the small number of prospective works with suitable sample and methodology, we have idealized the present study, that aims the evaluation of the suitability of the pH-meter distal sensor positioning based on the step-up technique, by analyzing the presence, the type and the degree of the error of positioning that such technique provides and the influence of the position adopted by the patient during the procedure. METHODS: One thousand and thirty one patients conducted to the esophageal pH-meter procedure were studied in a prospective way. During the clinical interview, the demographic data and the presented clinical complaints were registered. All the patients were submitted to both esophageal manometry in order to localize the lower esophageal sphincter and the pH step-up technique, that consists of the introduction of the pH-meter sensor in the gastric chamber and in the sensor's gradual traction until the pH steps up to levels over 4. The step-up point was identified by two distinct ways, characterizing two study groups: with the sitting patient (group I - 450 patients) and with the patient in supine position (group II - 581 patients). After the step-up point identification, the pH-meter distal sensor was placed in the standard position (based on the sphincter manometric placement). It was registered where the pH sensor would be positioned if the step-up technique were adopted. To evaluate the positioning suitability, the error was considered to be represented by the difference (in centimeters) between the suitable placement (manometry) and the one that would be adopted in case the step-up technique were adopted. The positioning error was considered rough if it were larger than 2 cm. The most frequent type of error was also analyzed (if above or below the standard position). RESULTS: It was observed that if the step-up technique were adopted, there would be error in the sensor positioning in 945 patients (91.6%). In terms of error degree, there would be a rough error in 597 (63.2%) cases. Concerning the type of error, the sensor would be positioned below the standard place in 857 (90.7%) patients. As to the interference of the position adopted by the patient during the step-up technique, it was observed that there was no significant difference among the groups of study in any of the analyzed parameters. CONCLUSIONS: 1. The positioning of the pH-meter distal sensor by the step-up technique is not reliable; 2. the step-up technique provides expressive error margin; 3. the most common type of error that such technique mode provides is the placement of the sensor below the standard positioning, which may overestimate the reflux occurrence; 4. there is no influence in the position adopted by the patient during the pH step-up technique procedure, in terms of method efficiency.

Saliva transport to the distal esophagus.

OBJECTIVE: During esophageal acid clearance, saliva should reach the most distal esophagus. The mechanisms responsible for saliva transport are not completely understood but it is assumed that normal peristalsis plays a significant role. The aim of this study was to assess the role of esophageal peristalsis and gravity in saliva transport to the distal esophagus. MATERIAL AND METHODS: Esophageal transit and presence times of a 2-ml bolus of radiolabeled artificial saliva were assessed using concurrent scintigraphy and manometry in 10 healthy volunteers in the upright and supine positions before and after disruption of esophageal motility with sildenafil (50 mg). RESULTS: With normal peristalsis, there was no difference in saliva transit to the distal esophagus between supine and upright positions 3.9 (1.5- >60.0) versus 3.3 s (1.3-8.3). Low amplitude contractions did not affect saliva transit but the disappearance of contractions after sildenafil was associated with prolonged saliva transit in supine position 7.4 (1.0- >60.0). Saliva presence time was significantly prolonged in both the upright and supine positions by esophageal dysmotility. CONCLUSIONS: Saliva transport to the distal esophagus does not require complete normal peristalsis or gravity and mainly depends on an efficient pharyngeal pump. However, subjects in supine position with severe esophageal dysmotility might have both impaired volume clearance and delayed saliva transport, leading to abnormal acid clearance and esophagitis.