Esophageal remodeling in eosinophilic esophagitis.

PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is a Th2 immune/antigen-mediated disorder characterized by esophageal dysfunction and eosinophilic inflammation. Worsening dysphagia and food impactions are significant complications associated with esophageal remodeling and fibrostenotic disease. This review highlights the most recent research findings pertaining to mechanisms of sub-epithelial fibrosis in EoE, current diagnostic tools, and therapeutic approaches. RECENT FINDINGS: Recent studies leveraging publicly available single cell sequencing databases and comparative proteomics have furthered our understanding of the mechanisms mediating fibrosis. Fibroblast crosstalk with the extracellular matrix and with epithelial, endothelial, and T cells have been implicated, with the likely existence of multiple fibroblast sub-types. Accurate diagnosis of remodeling with biopsies remains a challenge due to inadequate depth of sampling. Web-based tools incorporating epithelial findings show promise in predicting subepithelial fibrosis. Impedance planimetry with esophageal distensibility measurements are increasingly utilized tools to assess fibrostenotic severity. Immunostaining and luminal captured proteins associated with remodeling show promise as potential molecular markers of fibrosis. Anti-inflammatory therapy may improve esophageal fibrosis and distensibility, although specific fibrosis-targeted therapy is lacking. SUMMARY: Recent studies highlight novel mechanisms of fibrosis in EoE. Improved understanding of these mechanisms may lead to novel diagnostic strategies and therapies, and thereby inform treatment decisions.

Inflammatory and Proliferative Pathway Activation in Human Esophageal Myofibroblasts Treated with Acidic Bile Salts.

Subepithelial human esophageal myofibroblasts (HEMFs) in gastroesophageal reflux disease (GERD) are exposed to luminal contents via impaired squamous epithelium barrier integrity. The supernatant of HEMFs treated with acidic bile salts reflective of in vivo reflux increases squamous epithelial thickness. We aimed to identify the involved mechanisms using an unbiased approach. Acidic-bile-salt-treated primary HEMF cultures (n = 4) were submitted for RNA-Seq and analyzed with Partek Flow followed by Ingenuity Pathway Analysis (IPA). A total of 1165 molecules (579 downregulated, 586 upregulated) were differentially expressed, with most top regulated molecules either extracellular or in the plasma membrane. Increases in HEMF CXCL-8, IL-6, AREG, and EREG mRNA, and protein secretion were confirmed. Top identified canonical pathways were agranulocyte and granulocyte adhesion and diapedesis, PI3K/AKT signaling, CCR5 signaling in macrophages, and the STAT3 pathway. Top diseases and biological functions were cellular growth and development, hematopoiesis, immune cell trafficking, and cell-mediated response. The targets of the top upstream regulator ErbB2 included CXCL-8, IL-6, and AREG and the inhibition of CXCL-8 in the HEMF supernatant decreased squamous epithelial proliferation. Our work shows an inflammatory/immune cell and proliferative pathways activation in HEMFs in the GERD environment and identifies CXCL-8 as a HEMF-derived chemokine with paracrine proliferative effects on squamous epithelium.

Gender-Specific Risk Factors for Reflux Esophagitis in a Predominantly Hispanic Population of a Large Safety-Net Hospital.

BACKGROUND: Defining factors associated with severe reflux esophagitis allows for identification of subgroups most at risk for complications of strictures and esophageal malignancy. We hypothesized there might be unique clinical features in patients with reflux esophagitis in a predominantly Hispanic population of a large, safety-net hospital. AIM: Define clinical and endoscopic features of reflux esophagitis in a predominantly Hispanic population of a large, safety-net hospital. METHODS: This is retrospective comparative study of outpatients and hospitalized patients identified with mild (Los Angeles Grade A/B) and severe (Los Angeles Grade C/D) esophagitis through an endoscopy database review. The electronic medical record was reviewed for demographic and clinical data. RESULTS: Reflux esophagitis was identified in 382/5925 individuals: 56.5% males and 79.8% Hispanic. Multivariable logistic regression model adjusted for age, gender, race, body mass index (BMI), tobacco and alcohol use, and hospitalization status with severity as the outcome showed an interaction between gender and BMI (p ≤ 0.01). Stratification by gender showed that obese females had decreased odds of severe esophagitis compared to normal BMI females (OR = 0.18, 95% CI = 0.07-0.47; p < 0.01). In males, the odds of esophagitis were higher in inpatient status (OR = 2.84, 95% CI = 1.52 - 5.28; p < 0.01) and as age increased (OR = 1.37, 95% CI = 1.03 - 1.83; p = 0.03). CONCLUSIONS: We identify gender-specific associations with severe esophagitis in a predominantly Hispanic cohort. In females, obese BMI appears to be protective against severe esophagitis compared to normal BMI, while in men inpatient status and increasing age were associated with increased odds of severe esophagitis.

Human esophageal myofibroblasts secrete proinflammatory cytokines in response to acid and Toll-like receptor 4 ligands.

The pathophysiology of esophageal injury, repair, and inflammation in gastroesophageal reflux-disease (GERD) is complex. Whereas most studies have focused on the epithelial response to GERD injury, we are interested in the stromal response. We hypothesized that subepithelial esophageal myofibroblasts in GERD secrete proinflammatory cytokines in response to injurious agents encountered via epithelial barrier breaches or through dilated epithelial intercellular spaces. We determined the percentage of myofibroblasts [-smooth muscle actin (-SMA)+vimentin+CD31-] in the subepithelial GERD and normal esophageal stroma by immunomorphologic analysis. We performed -SMA coimmunostaining with IL-6 and p65. We established and characterized primary cultures of -SMA+vimentin+CD31-CD45- human esophageal myofibroblasts (HuEso MFs). We modeled GERD by treatment with pH 4.5-acidified media and Toll-like receptor 4 (TLR4) ligands, LPS and high-mobility group box 1 protein (HMGB1), and determined myofibroblast cytokine secretion in response to GERD injury. We demonstrate that spindle-shaped cell myofibroblasts are located near the basement membrane of stratified squamous epithelium in normal esophagus. We identify an increase in subepithelial myofibroblasts and activation of proinflammatory pathways in patients with GERD. Primary cultures of stromal cells obtained from normal esophagus retain myofibroblast morphology and express the acid receptor transient receptor potential channel vanilloid subfamily 1 (TRPV1) and TLR4. HuEso MFs stimulated with acid and TLR4 agonists LPS and HMGB1 increase IL-6 and IL-8 secretion via TRPV1 and NF-B activation. Our work implicates a role for human subepithelial stromal cells in the pathogenesis of GERD-related esophageal injury. Findings of this study can be extended to the investigation of epithelial-stromal interactions in inflammatory esophageal mucosal disorders.

Differential Contributions of Fibroblast Subpopulations to Intercellular Communication in Eosinophilic Esophagitis.

Fibroblast heterogeneity remains undefined in eosinophilic esophagitis (EoE), an allergic inflammatory disorder complicated by fibrosis. We utilized publicly available single-cell RNA sequencing data (GSE201153) of EoE esophageal biopsies to identify fibroblast sub-populations, related transcriptomes, disease status-specific pathways and cell-cell interactions. IL13-treated fibroblast cultures were used to model active disease. At least 2 fibroblast populations were identified, F_A and F_B. Several genes including ACTA2 were more enriched in F_A. F_B percentage was greater than F_A and epithelial-mesenchymal transition upregulated in F_B vs. F_A in active and remission EoE. Epithelial-mesenchymal transition was also upregulated in F_B in active vs. remission EoE and TNF-α signaling via NFKB was downregulated in F_A. IL-13 treatment upregulated ECM-related genes more profoundly in ACTA2- fibroblasts than ACTA2+ myofibroblasts. After proliferating epithelial cells, F_B and F_A contributed most to cell-cell communication networks. ECM-Receptor interaction strength was stronger than secreted or cell-cell contact signaling in active vs. remission EoE and significant ligand-receptor pairs were driven mostly by F_B. This unbiased analysis identifies at least 2 fibroblast sub-populations in EoE in vivo, distinguished in part by ACTA2. Fibroblasts play a critical role in cell-cell interactions in EoE, most profoundly via ECM-receptor signaling via the F_B sub-group.

Epimorphin deletion inhibits polyposis in the Apcmin/+ mouse model of colon carcinogenesis via decreased myofibroblast HGF secretion.

Interactions between the epithelium and surrounding mesenchyme/stroma play an important role in normal gut morphogenesis, the epithelial response to injury, and epithelial carcinogenesis. The tumor microenvironment, composed of stromal cells including myofibroblasts and immune cells, regulates tumor growth and the cancer stem cell niche. Deletion of epimorphin (Epim), a syntaxin family member expressed in myofibroblasts and macrophages, results in partial protection from colitis and from inflammation-induced colon cancer in mice. We sought to determine whether epimorphin deletion protects from polyposis in the Apcmin/+ mouse model of intestinal carcinogenesis. Epim-/- mice were crossed to Apcmin/+ mice; Apcmin/+ and Apcmin/+/Epim-/- mice were killed at 3 mo of age. Polyp numbers and sizes were quantified in small intestine and colon, and gene expression analyses for pathways relevant to epithelial carcinogenesis were performed. Primary myofibroblast cultures were isolated, and expression and secretion of selected growth factors from Apcmin/+ and Apcmin/+/Epim-/- myofibroblasts were examined by ELISA. Small bowel polyposis was significantly inhibited in Apcmin/+/Epim-/- compared with Apcmin/+ mice. Apcmin/+/Epim-/- compared with Apcmin/+ polyps and adjacent uninvolved intestinal mucosa had increased transforming growth factor-ß (TGF-ß) expression and signaling with increased P-Smad2/3 expression. Myofibroblasts isolated from Apcmin/+/Epim-/- vs. Apcmin/+ mice had markedly decreased hepatocyte growth factor (HGF) expression and secretion. We concluded that Epim deletion inhibits polyposis in Apcmin/+ mice, associated with increased mucosal TGF-ß signaling and decreased myofibroblast HGF expression and secretion. Our data suggest that Epim deletion reduces tumorigenicity of the stromal microenvironment.

Stromal cells participate in the murine esophageal mucosal injury response.

We identified α-smooth muscle actin (α-SMA)- and vimentin-expressing spindle-shaped esophageal mesenchymal cells in the adult and neonate murine esophageal lamina propria. We hypothesized that these esophageal mesenchymal cells express and secrete signaling and inflammatory mediators in response to injury. We established primary cultures of esophageal mesenchymal cells using mechanical and enzymatic digestion. We demonstrate that these primary cultures are nonhematopoietic, nonendothelial, stromal cells with myofibroblast-like features. These cells increase secretion of IL-6 in response to treatment with acidified media and IL-1ß. They also increase bone morphogenetic protein (Bmp)-4 secretion in response to sonic hedgehog. The location of these cells and their biological functions demonstrate their potential role in regulating esophageal epithelial responses to injury and repair.

Multiple rapid swallow responses during esophageal high-resolution manometry reflect esophageal body peristaltic reserve.

OBJECTIVES: Dysphagia may develop following antireflux surgery as a consequence of poor esophageal peristaltic reserve. We hypothesized that suboptimal contraction response following multiple rapid swallows (MRS) could be associated with chronic transit symptoms following antireflux surgery. METHODS: Wet swallow and MRS responses on esophageal high-resolution manometry (HRM) were characterized collectively in the esophageal body (distal contractile integral (DCI)), and individually in each smooth muscle contraction segment (S2 and S3 amplitudes) in 63 patients undergoing antireflux surgery and in 18 healthy controls. Dysphagia was assessed using symptom questionnaires. The MRS/wet swallow ratios were calculated for S2 and S3 peak amplitudes and DCI. MRS responses were compared in patients with and without late postoperative dysphagia following antireflux surgery. RESULTS: Augmentation of smooth muscle contraction (MRS/wet swallow ratios >1.0) as measured collectively by DCI was seen in only 11.1% with late postoperative dysphagia, compared with 63.6% in those with no dysphagia and 78.1% in controls (P≤0.02 for each comparison). Similar results were seen with S3 but not S2 peak amplitude ratios. Receiver operating characteristics identified a DCI MRS/wet swallow ratio threshold of 0.85 in segregating patients with late postoperative dysphagia from those with no postoperative dysphagia with a sensitivity of 0.67 and specificity of 0.64. CONCLUSIONS: Lack of augmentation of smooth muscle contraction following MRS is associated with late postoperative dysphagia following antireflux surgery, suggesting that MRS responses could assess esophageal smooth muscle peristaltic reserve. Further research is warranted to determine if antireflux surgery needs to be tailored to the MRS response.

Direct and indirect effects of alcohol and its toxic metabolite acetaldehyde on human esophageal myofibroblasts and epithelial cells.

BACKGROUND: Mechanisms by which alcohol increases the risk of esophageal squamous cell carcinoma remain undefined. Human esophageal myofibroblasts (HEMFs) subjacent to the squamous epithelium are exposed directly to these agents via epithelial barrier defects and indirectly via factors derived from the exposed epithelium. Our aim was to investigate the cellular biology of HEMFs and HEMF-esophageal epithelial cell interactions in response to alcohol and its toxic metabolite acetaldehyde. METHODS: An immortalized HEMF and a human esophageal epithelial cell line (Epi) were treated with alcohol (0 to 200 mM) or acetaldehyde (0 to 100 µM) in a cyclic fashion or incubated with supernatants collected from treated cells. Healthy cell %, reactive oxygen species (ROS), and proliferation were assessed via flow cytometry, luminescence, scratch wound, and colorimetric assays, respectively. A 15-plex multiplex assay was performed on cell supernatants, followed by IL-6 and IL-8 qRT-PCR and ELISA. RESULTS: Healthy HEMF decreased to less than 80% at 30 mM alcohol and 70 µM acetaldehyde, with microscopic changes at 40 µM acetaldehyde. HEMF ROS was detected at 100 mM alcohol and 80 µM acetaldehyde. Supernatants from 30 mM alcohol- or 40 µM acetaldehyde-treated HEMFs increased Epi proliferation more than two-fold that of lower doses. In the complementary studies, healthy Epi cells decreased to less than 80% at 50 mM and 70 µM acetaldehyde, with microscopic changes at 40 µM. Supernatants from Epi treated with 50 mM alcohol or 40 µM acetaldehyde increased HEMF proliferation more than two-fold that of lower doses. A multiplex assay of supernatants showed the greatest increase in concentrations of IL-6 and IL-8 in HEMFs and in Epi treated with higher doses of alcohol or acetaldehyde. Neutralization of IL-6 and IL-8 in supernatants of HEMFS and esophageal epithelial cells inhibited the proliferation of Epi and HEMFs, respectively. CONCLUSIONS: Alcohol and acetaldehyde doses in which the majority of HEMFs and epithelial cells are healthy, elicit the production of paracrine mediators with pro-proliferative effects on neighboring cells. Understanding the effect of alcohol and acetaldehyde on HEMFs and HEMF-epithelial interactions could help to identify the molecular basis by which alcohol increases the risk for esophageal cancer.

The Travels of Signet-Ring Cell Carcinoma: From Colon to Stomach and Duodenum.

Colorectal cancer (CRC) metastasizing to the stomach and duodenum is rare. Even rarer is when the CRC subtype is signet-ring cell carcinoma (SRCC). Endoscopic findings of CRC metastasis to the stomach have been described as solitary and submucosal while duodenal metastasis has been observed to be exophytic. In this report, we describe a case of a middle-aged man with colon SRCC presenting with oral intolerance. He was found to have concurrent metastases to the stomach and duodenum and died 8 months after his SRCC diagnosis.

The value of multiple rapid swallows during preoperative esophageal manometry before laparoscopic antireflux surgery.

BACKGROUND: When multiple swallows are rapidly administered, esophageal peristalsis is inhibited, and pronounced lower esophageal sphincter relaxation ensues. After the last swallow of the series, a robust contraction sequence results. The authors hypothesize that multiple rapid swallows (MRS) may have value in predicting esophageal transit symptoms in patients undergoing laparoscopic antireflux surgery (LARS). METHODS: Records of patients undergoing esophageal high-resolution manometry (HRM) before LARS were evaluated. The evaluation of MRS included adequate inhibitory response during swallows and the contraction pattern after MRS. Dysphagia was scored based on a product of symptom frequency and severity using 5-point Likert scales. A composite dysphagia score comprised the sum of scores for solid and liquid dysphagia, and a score of 4 or higher was considered clinically significant. The normal and abnormal MRS responses of patients with preoperative, early, and late postoperative dysphagia were compared with those of patients with no dysphagia. RESULTS: In this study, 63 patients (mean age, 60.3 ± 1.7 years, 48 women) undergoing HRM before LARS successfully performed MRS (median, 5 swallows; longest interval between swallows, 3.2 ± 0.1 s). After MRS, 14 patients (22.2%) had an intact peristaltic sequence. Complete failure of peristalsis was seen in 21 (33.3%), and incomplete esophageal inhibition in 25 (39.7%) of the remaining patients. When stratified by presence or absence of dysphagia, 58.3% of the subjects without dysphagia had a normal MRS response, whereas 83.3% had formation of peristaltic segments after MRS. In contrast, only 14% of the subjects with dysphagia had a normal MRS response (p ≤ 0.003 vs. the subjects with no dysphagia). Abnormal MRS responses were more prevalent in the patients with any preoperative and late postoperative dysphagia (p = 0.04 across groups) and in those with clinically significant dysphagia (p = 0.08 across groups). CONCLUSIONS: High-resolution manometry with MRS helps to predict dysphagia in subjects undergoing preoperative esophageal function testing before LARS.

Pattern of methane levels with lactulose breath testing; can we shorten the test duration?

BACKGROUND AND AIM: Methane levels in methane-positive lactulose breath tests are frequently elevated at time zero. We hypothesized that baseline methane level is sufficient to detect excessive methane production and thereby avoid extended testing. Our aim was to determine if baseline methane levels were sufficient to identify methane-positive individuals as defined by current guidelines. METHODS: A retrospective study of lactulose breath tests was conducted at an open access motility lab. A methane-positive study was defined as a methane level ≥10 ppm at any time. Small intestinal bacterial overgrowth (SIBO) was defined as a ≥20 ppm rise in hydrogen from baseline by 90 min. Dual-positive SIBO and methane studies were identified. Demographics, symptoms, and indications were recorded. RESULTS: Of 745 tests, 33.1%, 15.0%, and 3.1% were SIBO, methane, and dual-positive, respectively. Precisely 96.4% of methane-positive studies had methane levels ≥10 ppm within 90 min and 75.9% had levels ≥10 ppm at time 0. An additional elevation of ≥20 ppm over baseline within 90 min was observed in 32.1%. Of 22 methane-positive patients with constipation, methane levels were ≥10 ppm at baseline in 81.8% and were ≥10 ppm within 90 min in all cases. CONCLUSIONS: Nearly 25% of methane-positive studies were not identified by a fasting methane level, but 96% were identified within 90 min. Most methane-positive studies did not have a rise of 20 ppm above baseline. Our findings suggest the lactulose breath test for hydrogen and methane can be complete at 90 min.

Human esophageal myofibroblasts increase squamous epithelial thickness via paracrine mechanisms in an in vitro model of gastroesophageal reflux disease.

The pathogenesis of esophageal injury in gastroesophageal reflux disease (GERD) is incompletely understood. We modeled exposure of human esophageal myofibroblasts (HEMFs) to gastroesophageal reflux by repeated treatment with pH 4.5 and pH 4.5 bile salts and determined the effects on the epithelium in a 3D organotypic-like air-liquid interface model. Total, basal and supra-basal thickness of the epithelium were measured and immunostaining for p63, for basal (CK 14) and supra-basal (CK 4) squamous differentiation markers, and for cell proliferation (PCNA) were performed. Epithelial cell proliferation in response to HEMF conditioned media was also assessed in 2D culture. In the 3D organotypic model, total epithelial thickness increased similarly with pH 4.5 and pH 4.5 bile salt treated versus untreated and bile salt treated HEMF conditioned media. Epithelial p63 immunostaining was increased and multilayered. There was expansion of the CK14+ basal and CK4+ supra-basal layers in the epithelium established with conditioned media from pH 4.5 and pH 4.5 bile salt treated HEMFs versus untreated HEMF conditioned media. PCNA + cells per µm of tissue were unchanged in the basal layer across all treatment conditions while PCNA + cells per total DAPI + cells were decreased. In 2D culture, basal epithelial proliferation decreased with conditioned media from pH 4.5 and pH 4.5 bile salt treated HEMFs compared to conditioned media from untreated HEMF conditioned media. Secreted factors from HEMFs treated with acidic stimuli encountered in GERD increase epithelial thickness compared to secreted factors from untreated HEMFs and expand both basal and supra-basal layers. Our findings demonstrate for the first time paracrine regulation of the squamous epithelium from acid stimulated HEMFs. The effects of secreted factors from acid treated HEMFs on basal cell proliferation in this model and the mechanism mediating the increase in epithelial thickness merit further investigation.

Human esophageal myofibroblast secretion of bone morphogenetic proteins and GREMLIN1 and paracrine regulation of squamous epithelial growth.

We have previously shown myofibroblasts subjacent to the squamous epithelium in the normal human esophagus and an increase in esophagitis. Myofibroblast contribution to bone morphogenetic protein (BMP) signaling and to paracrine mediated epithelial-mesenchymal interactions in the human esophagus remains incompletely defined. We investigated BMP4 and BMP inhibitor GREM1 gene expression and protein levels in previously characterized human esophageal myofibroblast primary cultures and in a human esophageal myofibroblast cell line. We adapted human esophageal myofibroblast conditioned media into a 3D organotypic model to investigate the effect of myofibroblast secreted factors on squamous epithelial morphology, proliferation, differentiation and BMP signaling. Human esophageal myofibroblasts constitutively secrete GREM1 and increase BMP4 expression and BMP4 secretion in response to epithelial Hedgehog ligand SHH. Detection of secreted BMP4 is decreased in the presence of GREM1. Myofibroblast conditioned media increases epithelial proliferation and expression of basal markers p63 and CK14 leading to an overall increase in epithelial thickness. Epithelial BMP signaling increases with myofibroblast conditioned media. These findings were partially reversed with GREM1 inhibition. Our results demonstrate that myofibroblasts are potential sources of GREM1 and of BMP4 in the human esophagus and that human esophageal myofibroblast-epithelial paracrine interactions contribute in part to the regulation of epithelial growth.

Generation and Characterization of an Immortalized Human Esophageal Myofibroblast Line.

Stromal cells with a myofibroblast phenotype present in the normal human esophagus are increased in individuals with gastro-esophageal reflux disease (GERD). We have previously demonstrated that myofibroblasts stimulated with acid and TLR4 agonists increase IL-6 and IL-8 secretion using primary cultures of myofibroblasts established from normal human esophagus. While primary cultures have the advantage of reflecting the in vivo environment, a short life span and unavoidable heterogeneity limits the usefulness of this model in larger scale in vitro cellular signaling studies. The major aim of this paper therefore was to generate a human esophageal myofibroblast line with an extended lifespan. In the work presented here we have generated and characterized an immortalized human esophageal myofibroblast line by transfection with a commercially available GFP-hTERT lentivirus. Immortalized human esophageal myofibroblasts demonstrate phenotypic, genotypic and functional similarity to primary cultures of esophageal myofibroblasts we have previously described. We found that immortalized esophageal myofibroblasts retain myofibroblast spindle-shaped morphology at low and high confluence beyond passage 80, and express α-SMA, vimentin, and CD90 myofibroblast markers. Immortalized human esophageal myofibroblasts also express the putative acid receptor TRPV1 and TLR4 and retain the functional capacity to respond to stimuli encountered in GERD with secretion of IL-6. Finally, immortalized human esophageal myofibroblasts also support the stratified growth of squamous esophageal epithelial cells in 3D organotypic cultures. This newly characterized immortalized human esophageal myofibroblast cell line can be used in future cellular signaling and co-culture studies.

Provocative testing of the esophagus and its future.

Standard tests in clinical practice commonly fail to demonstrate a clear esophageal etiology for symptoms such as heartburn, dysphagia, or chest pain. Over the years, various provocative measures have been developed to provide a better understanding of the origins of such symptoms. Some measures, such as esophageal acid infusion or changing bolus consistency, can be easily incorporated into clinical practice. Others, such as multimodal stimulation systems, are more technically demanding. They have contributed to a better understanding of esophageal physiology in health and disease. Their role in clinical decision making is still evolving. This focused review provides a summary of the esophageal nociceptive pathways and how provocative testing can be used to interrogate their integrity.

Contribution of immunomodulators to gastroesophageal reflux disease and its complications: stromal cells, interleukin 4, and adiponectin.

Gastroesophageal reflux disease (GERD) has become the most commonly seen gastrointestinal disorder in outpatient clinics. In the United States, around 20% of the general population experience heartburn on a weekly basis. Although clinical complaints can be mild or moderate, patients with GERD may develop further complications, such as peptic strictures, Barrett's esophagus (BE), and even esophageal adenocarcinoma. Pathologically, GERD is developed as a result of chronic and enhanced exposure of the esophageal epithelium to noxious gastric refluxate. In this review article, we provide an overview of GERD and then focus on the roles of stromal cells, interleukin 4, and adiponectin in GERD and BE. The importance of inflammation and immunomodulators in GERD pathogenesis is highlighted. Targeting the immunomodulators or inflammation in general may improve the therapeutic outcome of GERD, in particular, in those refractory to proton pump inhibitors.

Pharmacological and other treatment modalities for esophageal pain.

Treatment of esophageal pain remains a major challenge for the clinician. Although many patients have heartburn and may respond to proton pump inhibitors, there in an unmet need for other treatment modalities in patients where there are no obvious pathological findings. Although analgesics are the mainstay in esophageal pain treatment, many patients are nonresponders to these drugs. The current concise review focuses on other systems affecting pain processing, where better understanding may serve as a framework for therapy. These are the parasympathetic nervous system, exercise, and personality profiles. Finally, treatment with analgesics for functional chest pain remains a challenge, and an overview of treatment with antidepressive drugs is provided.